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Sample records for peripheral sensory axons

  1. Myelinated sensory and alpha motor axon regeneration in peripheral nerve neuromas

    NASA Technical Reports Server (NTRS)

    Macias, M. Y.; Lehman, C. T.; Sanger, J. R.; Riley, D. A.

    1998-01-01

    Histochemical staining for carbonic anhydrase and cholinesterase (CE) activities was used to analyze sensory and motor axon regeneration, respectively, during neuroma formation in transected and tube-encapsulated peripheral nerves. Median-ulnar and sciatic nerves in the rodent model permitted testing whether a 4 cm greater distance of the motor neuron soma from axotomy site or intrinsic differences between motor and sensory neurons influenced regeneration and neuroma formation 10, 30, and 90 days later. Ventral root radiculotomy confirmed that CE-stained axons were 97% alpha motor axons. Distance significantly delayed axon regeneration. When distance was negligible, sensory axons grew out sooner than motor axons, but motor axons regenerated to a greater quantity. These results indicate regeneration differences between axon subtypes and suggest more extensive branching of motor axons within the neuroma. Thus, both distance from injury site to soma and inherent motor and sensory differences should be considered in peripheral nerve repair strategies.

  2. Myelinated sensory and alpha motor axon regeneration in peripheral nerve neuromas

    NASA Technical Reports Server (NTRS)

    Macias, M. Y.; Lehman, C. T.; Sanger, J. R.; Riley, D. A.

    1998-01-01

    Histochemical staining for carbonic anhydrase and cholinesterase (CE) activities was used to analyze sensory and motor axon regeneration, respectively, during neuroma formation in transected and tube-encapsulated peripheral nerves. Median-ulnar and sciatic nerves in the rodent model permitted testing whether a 4 cm greater distance of the motor neuron soma from axotomy site or intrinsic differences between motor and sensory neurons influenced regeneration and neuroma formation 10, 30, and 90 days later. Ventral root radiculotomy confirmed that CE-stained axons were 97% alpha motor axons. Distance significantly delayed axon regeneration. When distance was negligible, sensory axons grew out sooner than motor axons, but motor axons regenerated to a greater quantity. These results indicate regeneration differences between axon subtypes and suggest more extensive branching of motor axons within the neuroma. Thus, both distance from injury site to soma and inherent motor and sensory differences should be considered in peripheral nerve repair strategies.

  3. LAR receptor tyrosine phosphatases and HSPGs guide peripheral sensory axons to the skin

    PubMed Central

    Wang, Fang; Wolfson, Sean N.; Gharib, Arash; Sagasti, Alvaro

    2012-01-01

    Background Peripheral axons of somatosensory neurons innervate the skin early in development to detect touch stimuli. Embryological experiments had suggested that the skin produces guidance cues that attract sensory axons, but neither the attractants nor their neuronal receptors had previously been identified. Results To investigate peripheral axon navigation to the skin, we combined live imaging of developing zebrafish Rohon-Beard (RB) neurons with molecular loss-of-function manipulations. Simultaneously knocking down two members of the LAR family of receptor tyrosine phosphatases expressed in RB neurons, or inhibiting their function with dominant negative proteins, misrouted peripheral axons to internal tissues. Time-lapse imaging indicated that peripheral axon guidance, rather than outgrowth or maintenance, was defective in LAR deficient neurons. Peripheral axons displayed a similar misrouting phenotype in mutants defective in heparan sulfate proteoglycan (HSPG) production and avoided regions in which HSPGs were locally degraded. Conclusions HSPGs and LAR family receptors are required for sensory axon guidance to the skin. Together, our results support a model in which peripheral HSPGs are attractive ligands for LAR receptors on RB neurons. PMID:22326027

  4. Inhibition of Rho-kinase differentially affects axon regeneration of peripheral motor and sensory nerves.

    PubMed

    Joshi, Abhijeet R; Bobylev, Ilja; Zhang, Gang; Sheikh, Kazim A; Lehmann, Helmar C

    2015-01-01

    The small GTPase RhoA and its down-stream effector Rho-kinase (ROCK) are important effector molecules of the neuronal cytoskeleton. Modulation of the RhoA/ROCK pathway has been shown to promote axonal regeneration, however in vitro and animal studies are inconsistent regarding the extent of axonal outgrowth induced by pharmacological inhibition of ROCK. We hypothesized that injury to sensory and motor nerves result in diverse activation levels of RhoA, which may impact the response of those nerve fiber modalities to ROCK inhibition. We therefore examined the effects of Y-27632, a chemical ROCK inhibitor, on the axonal outgrowth of peripheral sensory and motor neurons grown in the presence of growth-inhibiting chondroitin sulfate proteoglycans (CSPGs). In addition we examined the effects of three different doses of Y-27632 on nerve regeneration of motor and sensory nerves in animal models of peripheral nerve crush. In vitro, sensory neurons were less responsive to Y-27632 compared to motor neurons in a non-growth permissive environment. These differences were associated with altered expression and activation of RhoA in sensory and motor axons. In vivo, systemic treatment with high doses of Y-27632 significantly enhanced the regeneration of motor axons over short distances, while the regeneration of sensory fibers remained largely unchanged. Our results support the concept that in a growth non-permissive environment, the regenerative capacity of sensory and motor axons is differentially affected by the RhoA/ROCK pathway, with motor neurons being more responsive compared to sensory. Future treatments, that are aimed to modulate RhoA activity, should consider this functional diversity.

  5. Peripheral Glia Have a Pivotal Role in the Initial Response to Axon Degeneration of Peripheral Sensory Neurons in Zebrafish

    PubMed Central

    Pope, Holly M.; Voigt, Mark M.

    2014-01-01

    Axon degeneration is a feature of many peripheral neuropathies. Understanding the organismal response to this degeneration may aid in identifying new therapeutic targets for treatment. Using a transgenic zebrafish line expressing a bacterial nitroreductase (Ntr)/mCherry fusion protein in the peripheral sensory neurons of the V, VII, IX, and X cranial nerves, we were able to induce and visualize the pathology of axon degeneration in vivo. Exposure of 4 days post fertilization Ntr larvae to the prodrug metronidazole (Met), which Ntr metabolizes into cytotoxic metabolites, resulted in dose-dependent cell death and axon degeneration. This was limited to the Ntr-expressing sensory neurons, as neighboring glia and motor axons were unaffected. Cell death was rapid, becoming apparent 3–4 hours after Met treatment, and was followed by phagocytosis of soma and axon debris by cells within the nerves and ganglia beginning at 4–5 hours of exposure. Although neutrophils appear to be activated in response to the degenerating neurons, they did not accumulate at the sites of degeneration. In contrast, macrophages were found to be attracted to the sites of the degenerating axons, where they phagocytosed debris. We demonstrated that peripheral glia are critical for both the phagocytosis and inflammatory response to degenerating neurons: mutants that lack all peripheral glia (foxD3−/−; Ntr) exhibit a much reduced reaction to axonal degeneration, resulting in a dramatic decrease in the clearance of debris, and impaired macrophage recruitment. Overall, these results show that this zebrafish model of peripheral sensory axon degeneration exhibits many aspects common to peripheral neuropathies and that peripheral glia play an important role in the initial response to this process. PMID:25058656

  6. Uptake of nerve growth factor along peripheral and spinal axons of primary sensory neurons

    SciTech Connect

    Richardson, P.M.; Riopelle, R.J.

    1984-07-01

    To investigate the distribution of nerve growth factor (NGF) receptors on peripheral and central axons, (/sup 125/I)NGF was injected into the sciatic nerve or spinal cord of adult rats. Accumulation of (/sup 125/I)NGF in lumbar dorsal root ganglia was monitored by gamma emission counting and radioautography. (/sup 125/I)NGF, injected endoneurially in small quantities, was taken into sensory axons by a saturable process and was transported retrogradely to their cell bodies at a maximal rate of 2.5 to 7.5 mm/hr. Because very little (/sup 125/I)NGF reached peripheral terminals, the results were interpreted to indicate that receptors for NGF are present on nonterminal segments of sensory axons. The specificity and high affinity of NGF uptake were illustrated by observations that negligible amounts of gamma activity accumulated in lumbar dorsal root ganglia after comparable intraneural injection of (/sup 125/I) cytochrome C or (/sup 125/I)oxidized NGF. Similar techniques were used to demonstrate avid internalization and retrograde transport of (/sup 125/I)NGF by intraspinal axons arising from dorsal root ganglia. Following injection of (/sup 125/I)NGF into lumbar or cervical regions of the spinal cord, neuronal perikarya were clearly labeled in radioautographs of lumbar dorsal root ganglia. Sites for NGF uptake on primary sensory neurons in the adult rat are not restricted to peripheral axon terminals but are extensively distributed along both peripheral and central axons. Receptors on axons provide a mechanism whereby NGF supplied by glia could influence neuronal maintenance or axonal regeneration.

  7. Peripheral Axons of the Adult Zebrafish Maxillary Barbel Extensively Remyelinate During Sensory Appendage Regeneration

    PubMed Central

    Moore, Alex C.; Mark, Tiffany E.; Hogan, Ann K.; Topczewski, Jacek; LeClair, Elizabeth E.

    2013-01-01

    Myelination is a cellular adaptation allowing rapid conduction along axons. We have investigated peripheral axons of the zebrafish maxillary barbel (ZMB), an optically clear sensory appendage. Each barbel carries taste buds, solitary chemosensory cells, and epithelial nerve endings, all of which regenerate after amputation (LeClair and Topczewski [2010] PLoS One 5:e8737). The ZMB contains axons from the facial nerve; however, myelination within the barbel itself has not been established. Transcripts of myelin basic protein (mbp) are expressed in normal and regenerating adult barbels, indicating activity in both maintenance and repair. Myelin was confirmed in situ by using toluidine blue, an anti-MBP antibody, and transmission electron microscopy (TEM). The adult ZMB contains ~180 small-diameter axons (<2 μm), approximately 60% of which are myelinated. Developmental myelination was observed via whole-mount immunohistochemistry 4-6 weeks postfertilization, showing myelin sheaths lagging behind growing axons. Early-regenerating axons (10 days postsurgery), having no or few myelin layers, were disorganized within a fibroblast-rich collagenous scar. Twenty-eight days postsurgery, barbel axons had grown out several millimeters and were organized with compact myelin sheaths. Fiber types and axon areas were similar between normal and regenerated tissue; within 4 weeks, regenerating axons restored ~85% of normal myelin thickness. Regenerating barbels express multiple promyelinating transcription factors (sox10, oct6 = pou3f1; krox20a/b = egr2a/b) typical of Schwann cells. These observations extend our understanding of the zebrafish peripheral nervous system within a little-studied sensory appendage. The accessible ZMB provides a novel context for studying axon regeneration, Schwann cell migration, and remyelination in a model vertebrate. PMID:22592645

  8. Novel roles for osteopontin and clusterin in peripheral motor and sensory axon regeneration.

    PubMed

    Wright, Megan C; Mi, Ruifa; Connor, Emmalynn; Reed, Nicole; Vyas, Alka; Alspalter, Manula; Coppola, Giovanni; Geschwind, Daniel H; Brushart, Thomas M; Höke, Ahmet

    2014-01-29

    Previous studies demonstrated that Schwann cells (SCs) express distinct motor and sensory phenotypes, which impact the ability of these pathways to selectively support regenerating neurons. In the present study, unbiased microarray analysis was used to examine differential gene expression in denervated motor and sensory pathways in rats. Several genes that were significantly upregulated in either denervated sensory or motor pathways were identified and two secreted factors were selected for further analysis: osteopontin (OPN) and clusterin (CLU) which were upregulated in denervated motor and sensory pathways, respectively. Sciatic nerve transection induced upregulation of OPN and CLU and expression of both returned to baseline levels with ensuing regeneration. In vitro analysis using exogenously applied OPN induced outgrowth of motor but not sensory neurons. CLU, however, induced outgrowth of sensory neurons, but not motor neurons. To assess the functional importance of OPN and CLU, peripheral nerve regeneration was examined in OPN and CLU(-/-) mice. When compared with OPN(+/+) mice, motor neuron regeneration was reduced in OPN(-/-) mice. Impaired regeneration through OPN(-/-) peripheral nerves grafted into OPN(+/+) mice indicated that loss of OPN in SCs was responsible for reduced motor regeneration. Sensory neuron regeneration was impaired in CLU(-/-) mice following sciatic nerve crush and impaired regeneration nerve fibers through CLU(-/-) nerve grafts transplanted into CLU(+/+) mice indicated that reduced sensory regeneration is likely due to SC-derived CLU. Together, these studies suggest unique roles for SC-derived OPN and CLU in regeneration of peripheral motor and sensory axons.

  9. Mitochondrial abnormality in sensory, but not motor, axons in paclitaxel-evoked painful peripheral neuropathy in the rat.

    PubMed

    Xiao, W H; Zheng, H; Zheng, F Y; Nuydens, R; Meert, T F; Bennett, G J

    2011-12-29

    The dose-limiting side effect of the anti-neoplastic agent, paclitaxel, is a chronic distal symmetrical peripheral neuropathy that produces sensory dysfunction (hypoesthesia and neuropathic pain) but little or no distal motor dysfunction. Similar peripheral neuropathies are seen with chemotherapeutics in the vinca alkaloid, platinum-complex, and proteasome inhibitor classes. Studies in rats suggest that the cause is a mitotoxic effect on axonal mitochondria. If so, then the absence of motor dysfunction may be due to mitotoxicity that affects sensory axons but spares motor axons. To investigate this, paclitaxel exposure levels in the dorsal root, ventral root, dorsal root ganglion, peripheral nerve, and spinal cord were measured, and the ultrastructure and the respiratory function of mitochondria in dorsal roots and ventral roots were compared. Sensory and motor axons in the roots and nerve had comparably low exposure to paclitaxel and exposure in the spinal cord was negligible. However, sensory neurons in the dorsal root ganglion had a very high and remarkably persistent (up to 10 days or more after the last injection) exposure to paclitaxel. Paclitaxel evoked a significant increase in the incidence of swollen and vacuolated mitochondria in the myelinated and unmyelinated sensory axons of the dorsal root (as seen previously in the peripheral nerve) but not in the motor axons of the ventral root. Stimulated mitochondrial respiration in the dorsal root was significantly depressed in paclitaxel-treated animals examined 2-4 weeks after the last injection, whereas respiration in the ventral root was normal. We conclude that the absence of motor dysfunction in paclitaxel-evoked peripheral neuropathy may be due to the absence of a mitotoxic effect in motor neuron axons, whereas the sensory dysfunction may be due to a mitotoxic effect resulting from the primary afferent neuron's cell body being exposed to high and persistent levels of paclitaxel.

  10. Comparison of the fastest regenerating motor and sensory myelinated axons in the same peripheral nerve.

    PubMed

    Moldovan, Mihai; Sørensen, Jesper; Krarup, Christian

    2006-09-01

    Functional outcome after peripheral nerve regeneration is often poor, particularly involving nerve injuries far from their targets. Comparison of sensory and motor axon regeneration before target reinnervation is not possible in the clinical setting, and previous experimental studies addressing the question of differences in growth rates of different nerve fibre populations led to conflicting results. We developed an animal model to compare growth and maturation of the fastest growing sensory and motor fibres within the same mixed nerve after Wallerian degeneration. Regeneration of cat tibial nerve after crush (n = 13) and section (n = 7) was monitored for up to 140 days, using implanted cuff electrodes placed around the sciatic and tibial nerves and wire electrodes at plantar muscles. To distinguish between sensory and motor fibres, recordings were carried out from L6-S2 spinal roots using cuff electrodes. The timing of laminectomy was based on the presence of regenerating fibres along the nerve within the tibial cuff. Stimulation of unlesioned tibial nerves (n = 6) evoked the largest motor response in S1 ventral root and the largest sensory response in L7 dorsal root. Growth rates were compared by mapping the regenerating nerve fibres within the tibial nerve cuff to all ventral or dorsal roots and, regardless of the lesion type, the fastest growth was similar in sensory and motor fibres. Maturation was assessed as recovery of the maximum motor and sensory conduction velocities (CVs) within the tibial nerve cuff. Throughout the observation period the CV was approximately 14% faster in regenerated sensory fibres than in motor fibres in accordance with the difference observed in control nerves. Recovery of amplitude was only partial after section, whereas the root distribution pattern was restored. Our data suggest that the fastest growth and maturation rates that can be achieved during regeneration are similar for motor and sensory myelinated fibres.

  11. Chronically CNS-injured adult sensory neurons gain regenerative competence upon a lesion of their peripheral axon.

    PubMed

    Ylera, Bhavna; Ertürk, Ali; Hellal, Farida; Nadrigny, Fabien; Hurtado, Andres; Tahirovic, Sabina; Oudega, Martin; Kirchhoff, Frank; Bradke, Frank

    2009-06-09

    Several experimental manipulations result in axonal regeneration in the central nervous system (CNS) when applied before or at the time of injury but not when initiated after a delay, which would be clinically more relevant. As centrally injured neurons show signs of atrophy and degeneration, it raises the question whether chronically injured neurons are able to regenerate. To address this question, we used adult rodent primary sensory neurons that regenerate their central axon when their peripheral axon is cut (called conditioning) beforehand but not afterwards. We found that primary sensory neurons express regeneration-associated genes and efficiently regrow their axon in cell culture two months after a central lesion upon conditioning. Moreover, conditioning enables central axons to regenerate through a fresh lesion independent of a previous central lesion. Using in vivo imaging we demonstrated that conditioned neurons rapidly regrow their axons through a fresh central lesion. Finally, when single sensory axons were cut with a two-photon laser, they robustly regenerate within days after attaining growth competence through conditioning. We conclude that sensory neurons can acquire the intrinsic potential to regenerate their axons months after a CNS lesion, which they implement in the absence of traumatic tissue.

  12. Polygenic Inheritance of Paclitaxel-Induced Sensory Peripheral Neuropathy Driven by Axon Outgrowth Gene Sets in CALGB 40101 (Alliance)

    PubMed Central

    Chhibber, Aparna; Mefford, Joel; Stahl, Eli A.; Pendergrass, Sarah A.; Baldwin, R. Michael; Owzar, Kouros; Li, Megan; Winer, Eric P.; Hudis, Clifford A.; Zembutsu, Hitoshi; Kubo, Michiaki; Nakamura, Yusuke; McLeod, Howard L.; Ratain, Mark J.; Shulman, Lawrence N.; Ritchie, Marylyn D.; Plenge, Robert M.; Witte, John S.; Kroetz, Deanna L.

    2014-01-01

    Peripheral neuropathy is a common dose-limiting toxicity for patients treated with paclitaxel. For most individuals there are no known risk factors that predispose patients to the adverse event, and pathogenesis for paclitaxel-induced peripheral neuropathy is unknown. Determining whether there is a heritable component to paclitaxel induced peripheral neuropathy would be valuable in guiding clinical decisions and may provide insight into treatment of and mechanisms for the toxicity. Using genotype and patient information from the paclitaxel arm of CALGB 40101 (Alliance), a phase III clinical trial evaluating adjuvant therapies for breast cancer in women, we estimated the variance in maximum grade and dose at first instance of sensory peripheral neuropathy. Our results suggest that paclitaxel-induced neuropathy has a heritable component, driven in part by genes involved in axon outgrowth. Disruption of axon outgrowth may be one of the mechanisms by which paclitaxel treatment results in sensory peripheral neuropathy in susceptible patients. PMID:24513692

  13. Polygenic inheritance of paclitaxel-induced sensory peripheral neuropathy driven by axon outgrowth gene sets in CALGB 40101 (Alliance).

    PubMed

    Chhibber, A; Mefford, J; Stahl, E A; Pendergrass, S A; Baldwin, R M; Owzar, K; Li, M; Winer, E P; Hudis, C A; Zembutsu, H; Kubo, M; Nakamura, Y; McLeod, H L; Ratain, M J; Shulman, L N; Ritchie, M D; Plenge, R M; Witte, J S; Kroetz, D L

    2014-08-01

    Peripheral neuropathy is a common dose-limiting toxicity for patients treated with paclitaxel. For most individuals, there are no known risk factors that predispose patients to the adverse event, and pathogenesis for paclitaxel-induced peripheral neuropathy is unknown. Determining whether there is a heritable component to paclitaxel-induced peripheral neuropathy would be valuable in guiding clinical decisions and may provide insight into treatment of and mechanisms for the toxicity. Using genotype and patient information from the paclitaxel arm of CALGB 40101 (Alliance), a phase III clinical trial evaluating adjuvant therapies for breast cancer in women, we estimated the variance in maximum grade and dose at first instance of sensory peripheral neuropathy. Our results suggest that paclitaxel-induced neuropathy has a heritable component, driven in part by genes involved in axon outgrowth. Disruption of axon outgrowth may be one of the mechanisms by which paclitaxel treatment results in sensory peripheral neuropathy in susceptible patients.

  14. Morphological Analysis of Drosophila Larval Peripheral Sensory Neuron Dendrites and Axons Using Genetic Mosaics

    PubMed Central

    Karim, M. Rezaul; Moore, Adrian W.

    2011-01-01

    Nervous system development requires the correct specification of neuron position and identity, followed by accurate neuron class-specific dendritic development and axonal wiring. Recently the dendritic arborization (DA) sensory neurons of the Drosophila larval peripheral nervous system (PNS) have become powerful genetic models in which to elucidate both general and class-specific mechanisms of neuron differentiation. There are four main DA neuron classes (I-IV)1. They are named in order of increasing dendrite arbor complexity, and have class-specific differences in the genetic control of their differentiation2-10. The DA sensory system is a practical model to investigate the molecular mechanisms behind the control of dendritic morphology11-13 because: 1) it can take advantage of the powerful genetic tools available in the fruit fly, 2) the DA neuron dendrite arbor spreads out in only 2 dimensions beneath an optically clear larval cuticle making it easy to visualize with high resolution in vivo, 3) the class-specific diversity in dendritic morphology facilitates a comparative analysis to find key elements controlling the formation of simple vs. highly branched dendritic trees, and 4) dendritic arbor stereotypical shapes of different DA neurons facilitate morphometric statistical analyses. DA neuron activity modifies the output of a larval locomotion central pattern generator14-16. The different DA neuron classes have distinct sensory modalities, and their activation elicits different behavioral responses14,16-20. Furthermore different classes send axonal projections stereotypically into the Drosophila larval central nervous system in the ventral nerve cord (VNC)21. These projections terminate with topographic representations of both DA neuron sensory modality and the position in the body wall of the dendritic field7,22,23. Hence examination of DA axonal projections can be used to elucidate mechanisms underlying topographic mapping7,22,23, as well as the wiring of a

  15. Morphological analysis of Drosophila larval peripheral sensory neuron dendrites and axons using genetic mosaics.

    PubMed

    Karim, M Rezaul; Moore, Adrian W

    2011-11-07

    Nervous system development requires the correct specification of neuron position and identity, followed by accurate neuron class-specific dendritic development and axonal wiring. Recently the dendritic arborization (DA) sensory neurons of the Drosophila larval peripheral nervous system (PNS) have become powerful genetic models in which to elucidate both general and class-specific mechanisms of neuron differentiation. There are four main DA neuron classes (I-IV)(1). They are named in order of increasing dendrite arbor complexity, and have class-specific differences in the genetic control of their differentiation(2-10). The DA sensory system is a practical model to investigate the molecular mechanisms behind the control of dendritic morphology(11-13) because: 1) it can take advantage of the powerful genetic tools available in the fruit fly, 2) the DA neuron dendrite arbor spreads out in only 2 dimensions beneath an optically clear larval cuticle making it easy to visualize with high resolution in vivo, 3) the class-specific diversity in dendritic morphology facilitates a comparative analysis to find key elements controlling the formation of simple vs. highly branched dendritic trees, and 4) dendritic arbor stereotypical shapes of different DA neurons facilitate morphometric statistical analyses. DA neuron activity modifies the output of a larval locomotion central pattern generator(14-16). The different DA neuron classes have distinct sensory modalities, and their activation elicits different behavioral responses(14,16-20). Furthermore different classes send axonal projections stereotypically into the Drosophila larval central nervous system in the ventral nerve cord (VNC)(21). These projections terminate with topographic representations of both DA neuron sensory modality and the position in the body wall of the dendritic field(7,22,23). Hence examination of DA axonal projections can be used to elucidate mechanisms underlying topographic mapping(7,22,23), as well as

  16. Identifying motor and sensory myelinated axons in rabbit peripheral nerves by histochemical staining for carbonic anhydrase and cholinesterase activities

    NASA Technical Reports Server (NTRS)

    Riley, Danny A.; Sanger, James R.; Matloub, Hani S.; Yousif, N. John; Bain, James L. W.

    1988-01-01

    Carbonic anhydrase (CA) and cholinesterase (CE) histochemical staining of rabbit spinal nerve roots and dorsal root ganglia demonstrated that among the reactive myeliated axons, with minor exceptions, sensory axons were CA positive and CE negative whereas motor axons were CA negative and CE positive. The high specificity was achieved by adjusting reaction conditions to stain subpopulations of myelinated axons selectively while leaving 50 percent or so unstained. Fixation with glutaraldehyde appeared necessary for achieving selectivity. Following sciatic nerve transection, the reciprocal staining pattern persisted in damaged axons and their regenerating processes which formed neuromas within the proximal nerve stump. Within the neuromas, CA-stained sensory processes were elaborated earlier and in greater numbers than CE-stained regenerating motor processes. The present results indicate that histochemical axon typing can be exploited to reveal heterogeneous responses of motor and sensory axons to injury.

  17. Identifying motor and sensory myelinated axons in rabbit peripheral nerves by histochemical staining for carbonic anhydrase and cholinesterase activities

    NASA Technical Reports Server (NTRS)

    Riley, Danny A.; Sanger, James R.; Matloub, Hani S.; Yousif, N. John; Bain, James L. W.

    1988-01-01

    Carbonic anhydrase (CA) and cholinesterase (CE) histochemical staining of rabbit spinal nerve roots and dorsal root ganglia demonstrated that among the reactive myeliated axons, with minor exceptions, sensory axons were CA positive and CE negative whereas motor axons were CA negative and CE positive. The high specificity was achieved by adjusting reaction conditions to stain subpopulations of myelinated axons selectively while leaving 50 percent or so unstained. Fixation with glutaraldehyde appeared necessary for achieving selectivity. Following sciatic nerve transection, the reciprocal staining pattern persisted in damaged axons and their regenerating processes which formed neuromas within the proximal nerve stump. Within the neuromas, CA-stained sensory processes were elaborated earlier and in greater numbers than CE-stained regenerating motor processes. The present results indicate that histochemical axon typing can be exploited to reveal heterogeneous responses of motor and sensory axons to injury.

  18. Mechanosensilla in the adult abdomen of Drosophila: engrailed and slit help to corral the peripheral sensory axons into segmental bundles.

    PubMed

    Fabre, Caroline C G; Casal, José; Lawrence, Peter A

    2010-09-01

    The abdomen of adult Drosophila bears mechanosensory bristles with axons that connect directly to the CNS, each hemisegment contributing a separate nerve bundle. Here, we alter the amount of Engrailed protein and manipulate the Hedgehog signalling pathway in clones of cells to study their effects on nerve pathfinding within the peripheral nervous system. We find that high levels of Engrailed make the epidermal cells inhospitable to bristle neurons; sensory axons that are too near these cells are either deflected or fail to extend properly or at all. We then searched for the engrailed-dependent agent responsible for these repellent properties. We found slit to be expressed in the P compartment and, using genetic mosaics, present evidence that Slit is the responsible molecule. Blocking the activity of the three Robo genes (putative receptors for Slit) with RNAi supported this hypothesis. We conclude that, during normal development, gradients of Slit protein repel axons away from compartment boundaries - in consequence, the bristles from each segment send their nerves to the CNS in separated sets.

  19. Pathways regulating modality-specific axonal regeneration in peripheral nerve.

    PubMed

    Wood, Matthew D; Mackinnon, Susan E

    2015-03-01

    Following peripheral nerve injury, the distal nerve is primed for regenerating axons by generating a permissive environment replete with glial cells, cytokines, and neurotrophic factors to encourage axonal growth. However, increasing evidence demonstrates that regenerating axons within peripheral nerves still encounter axonal-growth inhibitors, such as chondroitin sulfate proteoglycans. Given the generally poor clinical outcomes following peripheral nerve injury and reconstruction, the use of pharmacological therapies to augment axonal regeneration and overcome inhibitory signals has gained considerable interest. Joshi et al. (2014) have provided evidence for preferential or modality-specific (motor versus sensory) axonal growth and regeneration due to inhibitory signaling from Rho-associated kinase (ROCK) pathway regulation. By providing inhibition to the ROCK signaling pathway through Y-27632, they demonstrate that motor neurons regenerating their axons are impacted to a greater extent compared to sensory neurons. In light of this evidence, we briefly review the literature regarding modality-specific axonal regeneration to provide context to their findings. We also describe potential and novel barriers, such as senescent Schwann cells, which provide additional axonal-growth inhibitory factors for future consideration following peripheral nerve injury.

  20. CNS axons globally increase axonal transport after peripheral conditioning.

    PubMed

    Mar, Fernando M; Simões, Anabel R; Leite, Sérgio; Morgado, Marlene M; Santos, Telma E; Rodrigo, Inês S; Teixeira, Carla A; Misgeld, Thomas; Sousa, Mónica M

    2014-04-23

    Despite the inability of CNS axons to regenerate, an increased regenerative capacity can be elicited following conditioning lesion to the peripheral branch of dorsal root ganglia neurons (DRGs). By in vivo radiolabeling of rat DRGs, coupled to mass spectrometry and kinesin immunoprecipitation of spinal cord extracts, we determined that the anterograde transport of cytoskeleton components, metabolic enzymes and axonal regeneration enhancers, was increased in the central branch of DRGs following a peripheral conditioning lesion. Axonal transport of mitochondria was also increased in the central branch of Thy1-MitoCFP mice following a peripheral injury. This effect was generalized and included augmented transport of lysosomes and synaptophysin- and APP-carrying vesicles. Changes in axonal transport were only elicited by a peripheral lesion and not by spinal cord injury. In mice, elevated levels of motors and of polyglutamylated and tyrosinated tubulin were present following a peripheral lesion and can explain the increase in axonal transport induced by conditioning. In summary, our work shows that a peripheral injury induces a global increase in axonal transport that is not restricted to the peripheral branch, and that, by extending to the central branch, allows a rapid and sustained support of regenerating central axons.

  1. Bioenergetic deficits in peripheral nerve sensory axons during chemotherapy-induced neuropathic pain resulting from peroxynitrite-mediated post-translational nitration of mitochondrial superoxide dismutase

    PubMed Central

    Janes, Kali; Doyle, Timothy; Bryant, Leesa; Esposito, Emanuela; Cuzzocrea, Salvatore; Ryerse, Jan; Bennett, Gary J.; Salvemini, Daniela

    2016-01-01

    Many of the widely used anticancer drugs induce dose-limiting peripheral neuropathies that undermine their therapeutic efficacy. Animal models of chemotherapy-induced painful peripheral neuropathy (CIPN) evoked by a variety of drug classes, including taxanes, vinca alkaloids, platinum-complexes, and proteasome-inhibitors, suggest that the common underlying mechanism in the development of these neuropathies is mitotoxicity in primary nerve sensory axons (PNSAs) arising from reduced mitochondrial bioenergetics [eg adenosine triphosphate (ATP) production deficits due to compromised respiratory complex I and II activity]. The causative mechanisms of this mitotoxicity remain poorly defined. However, peroxynitrite, an important pro-nociceptive agent, has been linked to mitotoxicity in several disease states and may also drive the mitotoxicity associated with CIPN. Our findings reveal that the development of mechano-hypersensitivity induced by paclitaxel, oxaliplatin, and bortezomib was prevented by administration of the peroxynitrite decomposition catalyst Mn(III) 5,10,15,20-tetrakis(N-n-hexylpyridinium-2-yl)porphyrin (MnTE-2-PyP5+) without interfering with their anti-tumor effects. Peak CIPN was associated with the nitration and inactivation of superoxide dismutase in the mitochondria, but not in the cytosol, as well as a significant decrease in ATP production within the PNSAs; all of these events were attenuated by MnTE-2-PyP5+. Our results provide continued support for the role of mitotoxicity in the development of CIPN across chemotherapeutic drug classes, and identify peroxynitrite as a key mediator in these processes, thereby providing the rationale towards development of “peroxynitrite-targeted” therapeutics for CIPN. PMID:23891899

  2. Exercise dependent increase in axon regeneration into peripheral nerve grafts by propriospinal but not sensory neurons after spinal cord injury is associated with modulation of regeneration-associated genes.

    PubMed

    Sachdeva, Rahul; Theisen, Catherine C; Ninan, Vinu; Twiss, Jeffery L; Houlé, John D

    2016-02-01

    Insufficient regeneration of central nervous system (CNS) axons contributes to persisting neurological dysfunction after spinal cord injury (SCI). Peripheral nerve grafts (PNGs) support regeneration by thousands of injured intraspinal axons and help them bypass some of the extracellular barriers that form after SCI. However this number represents but a small portion of the total number of axons that are injured. Here we tested if rhythmic sensory stimulation during cycling exercise would boost the intrinsic regenerative state of neurons to enhance axon regeneration into PNGs after a lower thoracic (T12) spinal transection of adult rats. Using True Blue retrograde tracing, we show that 4 weeks of cycling improves regeneration into a PNG from lumbar interneurons but not by primary sensory neurons. The majority of neurons that regenerate their axon are within 5 mm of the lesion and their number increased 70% with exercise. Importantly propriospinal neurons in more distant regions (5-20 mm from the lesion) that routinely exhibit very limited regeneration responded to exercise by increasing the number of regenerating neurons by 900%. There was no exercise-associated increase in regeneration from sensory neurons. Analyses using fluorescent in situ hybridization showed that this increase in regenerative response is associated with changes in levels of mRNAs encoding the regeneration associated genes (RAGs) GAP43, β-actin and Neuritin. While propriospinal neurons showed increased mRNA levels in response to SCI alone and then to grafting and exercise, sensory neurons did not respond to SCI, but there was a response to the presence of a PNG. Thus, exercise is a non-invasive approach to modulate gene expression in injured neurons leading to an increase in regeneration. This sets the stage for future studies to test whether exercise will promote axon outgrowth beyond the PNG and reconnection with spinal cord neurons, thereby demonstrating a potential clinical application of

  3. Exercise dependent increase in axon regeneration into peripheral nerve grafts by propriospinal but not sensory neurons after spinal cord injury is associated with modulation of regeneration-associated genes

    PubMed Central

    Sachdeva, Rahul; Theisen, Catherine C.; Ninan, Vinu; Twiss, Jeffery L.; Houlé, John D.

    2015-01-01

    Insufficient regeneration of central nervous system (CNS) axons contributes to persisting neurological dysfunction after spinal cord injury (SCI). Peripheral nerve grafts (PNGs) support regeneration by thousands of injured intraspinal axons and help them bypass some of the extracellular barriers that form after SCI. However this number represents but a small portion of the total number of axons that are injured. Here we tested if rhythmic sensory stimulation during cycling exercise would boost the intrinsic regenerative state of neurons to enhance axon regeneration into PNGs after a lower thoracic (T12) spinal transection of adult rats. Using True Blue retrograde tracing, we show that 4 weeks of cycling improves regeneration into a PNG from lumbar interneurons but not by primary sensory neurons. The majority of neurons that regenerate their axon are within 5mm of the lesion and their number increased 70% with exercise. Importantly propriospinal neurons in more distant regions (5–20 mm from the lesion) that routinely exhibit very limited regeneration responded to exercise by increasing the number of regenerating neurons by 900%. There was no exercise-associated increase in regeneration from sensory neurons. Analyses using fluorescent in situ hybridization showed that this increase in regenerative response is associated with changes in levels of mRNAs encoding the regeneration associated genes (RAGs) GAP43, β-actin and Neuritin. While propriospinal neurons showed increased mRNA levels in response to SCI alone and then to grafting and exercise, sensory neurons did not respond to SCI, but there was a response to the presence of a PNG. Thus, exercise is a non-invasive approach to modulate gene expression in injured neurons leading to an increase in regeneration. This sets the stage for future studies to test whether exercise will promote axon outgrowth beyond the PNG and reconnection with spinal cord neurons, thereby demonstrating a potential clinical application of

  4. Characterizing Semaphorin-Mediated Effects on Sensory and Motor Axon Pathfinding and Connectivity During Embryonic Development.

    PubMed

    Huettl, Rosa Eva; Huber, Andrea B

    2017-01-01

    How are precise connectivity to peripheral targets and corresponding sensory-motor networks established during developmental innervation of the vertebrate extremities? The formation of functional sensory-motor circuits requires highly appropriate temporal and spatial regulation of axon growth which is achieved through the combination of different molecular mechanisms such as communication between heterotypic fiber systems, axon-environment, or axon-glia interactions that ensure proper fasciculation and accurate pathfinding to distal targets. Family members of the class 3 semaphorins and their cognate receptors, the neuropilins, were shown to govern various events during wiring of central and peripheral circuits, with mice lacking Sema3-Npn signaling showing deficits in timing of growth, selective fasciculation, guidance fidelity, and coupling of sensory axon growth to motor axons at developmental time points. Given the accuracy with which these processes have to interact in a stepwise manner, deficiency of the smallest cog in the wheel may impact severely on the faithful establishment and functionality of peripheral circuitries, ultimately leading to behavioral impairments or even cause the death of the animal. Reliable quantitative analyses of sensory-motor fasciculation, extension, and guidance of axons to their cognate target muscles and the skin during development, but also assessment of physiological and behavioral consequences at adult age, are therefore a necessity to extend our understanding of the molecular mechanisms of peripheral circuit formation. In this chapter we provide a detailed methodology to characterize class 3 semaphorin-mediated effects on peripheral sensory and motor axon pathfinding and connectivity during embryonic development.

  5. Eph:ephrin-B1 forward signaling controls fasciculation of sensory and motor axons.

    PubMed

    Luxey, Maëva; Jungas, Thomas; Laussu, Julien; Audouard, Christophe; Garces, Alain; Davy, Alice

    2013-11-15

    Axon fasciculation is one of the processes controlling topographic innervation during embryonic development. While axon guidance steers extending axons in the accurate direction, axon fasciculation allows sets of co-extending axons to grow in tight bundles. The Eph:ephrin family has been involved both in axon guidance and fasciculation, yet it remains unclear how these two distinct types of responses are elicited. Herein we have characterized the role of ephrin-B1, a member of the ephrinB family in sensory and motor innervation of the limb. We show that ephrin-B1 is expressed in sensory axons and in the limb bud mesenchyme while EphB2 is expressed in motor and sensory axons. Loss of ephrin-B1 had no impact on the accurate dorso-ventral innervation of the limb by motor axons, yet EfnB1 mutants exhibited decreased fasciculation of peripheral motor and sensory nerves. Using tissue-specific excision of EfnB1 and in vitro experiments, we demonstrate that ephrin-B1 controls fasciculation of axons via a surround repulsion mechanism involving growth cone collapse of EphB2-expressing axons. Altogether, our results highlight the complex role of Eph:ephrin signaling in the development of the sensory-motor circuit innervating the limb.

  6. Differences in excitability between median and superficial radial sensory axons.

    PubMed

    Fujimaki, Yumi; Kanai, Kazuaki; Misawa, Sonoko; Shibuya, Kazumoto; Isose, Sagiri; Nasu, Saiko; Sekiguchi, Yukari; Ohmori, Shigeki; Noto, Yu-ichi; Kugio, Yumiko; Shimizu, Toshio; Matsubara, Shiro; Lin, Cindy S Y; Kuwabara, Satoshi

    2012-07-01

    The aim of this study was to investigate differences in excitability properties of human median and superficial radial sensory axons (e.g., axons innervating the glabrous and hairy skin in the hand). Previous studies have shown that excitability properties differ between motor and sensory axons, and even among sensory axons between median and sural sensory axons. In 21 healthy subjects, threshold tracking was used to examine excitability indices such as strength-duration time constant, threshold electrotonus, supernormality, and threshold change at the 0.2 ms inter-stimulus interval in latent addition. In addition, threshold changes induced by ischemia for 10 min were compared between median and superficial radial sensory axons. Compared with radial sensory axons, median axons showed shorter strength-duration time constant, greater threshold changes in threshold electrotonus (fanning-out), greater supernormality, and smaller threshold changes in latent addition. Threshold changes in both during and after ischemia were greater for median axons. These findings suggest that membrane potential in human median sensory axons is more negative than in superficial radial axons, possibly due to greater activity of electrogenic Na(+)/K(+) pump. These results may reflect adaptation to impulses load carried by median axons that would be far greater with a higher frequency. Biophysical properties are not identical in different human sensory axons, and therefore their responses to disease may differ. Copyright © 2011 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

  7. Sensory Coding in Oscillatory Peripheral Receptors

    NASA Astrophysics Data System (ADS)

    Neiman, Alexander

    2014-03-01

    Rhythmical activity have been observed in several types of peripheral sensory receptors, e.g. in senses of hearing, balance and electroreception. We use two examples of spontaneously oscillating peripheral sensory receptors: bullfrog saccular hair cells and electroreceptors of paddlefish, to discuss how oscillations emerge, how these sensors may utilize oscillations to optimize their sensitivity and information processing. In the hair cell system oscillations occur on two very different levels: first, the mechano-sensory hair bundle itself can undergo spontaneous mechanical oscillations and second, self-sustained voltage oscillations across the membrane of the hair cell have been documented. Modelling show that interaction of these two compartment results in enhanced sensitivity to periodic mechanical stimuli. The second example, a single peripheral electroreceptor, is a complex system comprised of several thousands of sensory epithelial cells innervated by a few primary sensory neurons. It embeds two distinct oscillators: one residing in a population of epithelial cells, synaptically coupled to another oscillator residing in a branched myelinated afferent axon. We show how neuronal oscillations emerge in a complex network of excitable nodes. We further demonstrate that epithelial oscillations results in extended serial correlations of neruonal discharges enhancing coding of external stimuli.

  8. Concomitant Acute Transverse Myelitis and Sensory Motor Axonal Polyneuropathy in Two Children: Two Case Reports

    PubMed Central

    Chung, Hyung; Joa, Kyung-Lim; Kim, Hyo-Sang; Kim, Chang-Hwan; Jung, Han-Young

    2015-01-01

    Acute transverse myelitis (ATM) is an upper motor neuron disease of the spinal cord, and concomitant association of peripheral polyneuropathy, particularly the axonal type, is rarely reported in children. Our cases presented with ATM complicated with axonal type polyneuropathy. Axonal type polyneuropathy may be caused by acute motor-sensory axonal neuropathy (AMSAN) or critical illness polyneuropathy and myopathy (CIPNM). These cases emphasize the need for nerve and muscle biopsies to make the differential diagnosis between AMSAN and CIPNM in patients with ATM complicated with axonal polyneuropathy. PMID:25750885

  9. Sensory correlates of pain in peripheral neuropathies.

    PubMed

    Ng Wing Tin, Sophie; Ciampi de Andrade, Daniel; Goujon, Colette; Planté-Bordeneuve, Violaine; Créange, Alain; Lefaucheur, Jean-Pascal

    2014-05-01

    To characterize sensory threshold alterations in peripheral neuropathies and the relationship between these alterations and the presence of pain. Seventy-four patients with length-dependent sensory axonal neuropathy were enrolled, including 38 patients with painful neuropathy (complaining of chronic, spontaneous neuropathic pain in the feet) and 36 patients with painless neuropathy. They were compared to 28 age-matched normal controls. A standardized quantitative sensory testing protocol was performed in all individuals to assess large and small fiber function at the foot. Large fibers were assessed by measuring mechanical (pressure and vibration) detection thresholds and small fibers by measuring pain and thermal detection thresholds. Between patients with neuropathy and controls, significant differences were found for mechanical and thermal detection thresholds but not for pain thresholds. Patients with painful neuropathy and those with painless neuropathy did not differ regarding mechanical or thermal thresholds, but only by a higher incidence of thermal or dynamic mechanical allodynia in case of painful neuropathy. Pain intensity correlated with the alteration of thermal detection and mechanical pain thresholds. Quantitative sensory testing can support the diagnosis of sensory neuropathy when considering detection threshold measurement. Thermal threshold deterioration was not associated with the occurrence of pain but with its intensity. There is a complex relationship between the loss or functional deficit of large and especially small sensory nerve fibers and the development of pain in peripheral neuropathy. Copyright © 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

  10. Reversible isolated sensory axonal neuropathy due to cobalamin deficiency.

    PubMed

    Dalla Torre, Chiara; Lucchetta, Marta; Cacciavillani, Mario; Campagnolo, Marta; Manara, Renzo; Briani, Chiara

    2012-03-01

    Vitamin B(12) deficiency causes a wide range of hematological, gastrointestinal, and neurological manifestations. The most common neurological complication is subacute combined degeneration, sometimes associated with polyneuropathy. Isolated peripheral neuropathy due to cyanocobalamin deficiency is less frequent, and thus it may be overlooked. We describe 2 patients with isolated sensory axonal neuropathy secondary to vitamin B(12) deficiency who had complete clinical and electrophysiological recovery after cyanocobalamin replacement. Testing for serum vitamin B(12) and its metabolites should be done in any distal symmetric neuropathy. Copyright © 2011 Wiley Periodicals, Inc.

  11. Paclitaxel causes degeneration of both central and peripheral axon branches of dorsal root ganglia in mice.

    PubMed

    Tasnim, Aniqa; Rammelkamp, Zoe; Slusher, Amy B; Wozniak, Krystyna; Slusher, Barbara S; Farah, Mohamed H

    2016-07-11

    Peripheral neuropathy is a common and dose-limiting side effect of many cancer chemotherapies. The taxane agents, including paclitaxel (Taxol(®)), are effective chemotherapeutic drugs but cause degeneration of predominantly large myelinated afferent sensory fibers of the peripheral nervous system in humans and animal models. Dorsal root ganglia (DRG) neurons are sensory neurons that have unipolar axons each with two branches: peripheral and central. While taxane agents induce degeneration of peripheral axons, whether they also cause degeneration of central nervous system axons is not clear. Using a mouse model of paclitaxel-induced neuropathy, we investigated the effects of paclitaxel on the central branches of sensory axons. We observed that in the spinal cords of paclitaxel-intoxicated mice, degenerated axons were present in the dorsal columns, where the central branches of DRG axons ascend rostrally. In the peripheral nerves, degenerated myelinated fibers were present in significantly greater numbers in distal segments than in proximal segments indicating that this model exhibits the distal-to-proximal degeneration pattern generally observed in human peripheral nerve disorders. We conclude that paclitaxel causes degeneration of both the peripheral and central branches of DRG axons, a finding that has implications for the site and mode of action of chemotherapy agents on the nervous system.

  12. Axonal transport disruption in peripheral nerve disease

    PubMed Central

    Lloyd, Thomas E.

    2015-01-01

    Many neurodegenerative diseases and neuropathies have been proposed to be caused by a disruption of axonal transport. However, the mechanisms whereby impaired transport causes disease remain unclear. Proposed mechanisms include impairment in delivery of organelles such as mitochondria, defective retrograde neurotrophic signaling, and disruption of the synaptic vesicle cycle within the synaptic terminal. Simple model organisms such as the fruitfly, Drosophila melanogaster, allow live imaging of axonal transport to be combined with high-throughput genetic screens and are providing insights into the pathophysiology of peripheral nerve diseases. PMID:23279432

  13. A templated agarose scaffold for axon guidance in the central and peripheral nervous system

    NASA Astrophysics Data System (ADS)

    Gros, Thomas Richard

    This thesis examined the hypothesis that axonal guidance could be improved in the central and peripheral nervous systems using a highly linearized templated agarose scaffold. In the present study we examined whether a templated agarose scaffold improved axon retention across a large central nervous system (CNS) lesion and how cellular and axonal orientation was affected within the scaffold channels. The "physical" guidance from the scaffold was applied to an existing CNS "chemical" guidance strategy, shown to promote axons beyond the lesion site, to enhance the number of crossing axons in larger, disorganized, lesions. Specifically, there was the greatest number of long-tract sensory axons reaching the distal aspect of the lesion when the templated agarose scaffold was combined with a neurotrophic source of NT-3 beyond the lesion site and a conditioning lesion, to enhance chemical axon guidance and the intrinsic growth state of axons, respectively. When comparing the scaffold implant to a cell suspension grafts, we found a higher retention of long-tract ascending (sensory) axons and descending (motor) axons crossing large lesions (2mm). The enhanced axon retention may be attributed to the finding that cellular orientation within the scaffold channels is highly linear, thus promoting a less tortuous environment for axon orientation and bridging. Although an enhanced number of axons were able to cross the lesion, the axons did not repenetrate the host tissue due to a reactive cell layer, present only in scaffold the implant groups. Additionally, a peripheral nerve conduit, with the agarose scaffold as the core, displayed biocompatiablility and supported axon growth and vasculature beyond the clinically applicable distance of 4mm. Thus, the templated agarose scaffold enhances axon retention and guidance within CNS injury sites and has potential applications to the PNS.

  14. Preferential Enhancement of Sensory and Motor Axon Regeneration by Combining Extracellular Matrix Components with Neurotrophic Factors

    PubMed Central

    Santos, Daniel; González-Pérez, Francisco; Giudetti, Guido; Micera, Silvestro; Udina, Esther; Del Valle, Jaume; Navarro, Xavier

    2016-01-01

    After peripheral nerve injury, motor and sensory axons are able to regenerate but inaccuracy of target reinnervation leads to poor functional recovery. Extracellular matrix (ECM) components and neurotrophic factors (NTFs) exert their effect on different neuronal populations creating a suitable environment to promote axonal growth. Here, we assessed in vitro and in vivo the selective effects of combining different ECM components with NTFs on motor and sensory axons regeneration and target reinnervation. Organotypic cultures with collagen, laminin and nerve growth factor (NGF)/neurotrophin-3 (NT3) or collagen, fibronectin and brain-derived neurotrophic factor (BDNF) selectively enhanced sensory neurite outgrowth of DRG neurons and motor neurite outgrowth from spinal cord slices respectively. For in vivo studies, the rat sciatic nerve was transected and repaired with a silicone tube filled with a collagen and laminin matrix with NGF/NT3 encapsulated in poly(lactic-co-glycolic acid) (PLGA) microspheres (MP) (LM + MP.NGF/NT3), or a collagen and fibronectin matrix with BDNF in PLGA MPs (FN + MP.BDNF). Retrograde labeling and functional tests showed that LM + MP.NGF/NT3 increased the number of regenerated sensory neurons and improved sensory functional recovery, whereas FN + MP.BDNF preferentially increased regenerated motoneurons and enhanced motor functional recovery. Therefore, combination of ECM molecules with NTFs may be a good approach to selectively enhance motor and sensory axons regeneration and promote appropriate target reinnervation. PMID:28036084

  15. Preferential Enhancement of Sensory and Motor Axon Regeneration by Combining Extracellular Matrix Components with Neurotrophic Factors.

    PubMed

    Santos, Daniel; González-Pérez, Francisco; Giudetti, Guido; Micera, Silvestro; Udina, Esther; Del Valle, Jaume; Navarro, Xavier

    2016-12-29

    After peripheral nerve injury, motor and sensory axons are able to regenerate but inaccuracy of target reinnervation leads to poor functional recovery. Extracellular matrix (ECM) components and neurotrophic factors (NTFs) exert their effect on different neuronal populations creating a suitable environment to promote axonal growth. Here, we assessed in vitro and in vivo the selective effects of combining different ECM components with NTFs on motor and sensory axons regeneration and target reinnervation. Organotypic cultures with collagen, laminin and nerve growth factor (NGF)/neurotrophin-3 (NT3) or collagen, fibronectin and brain-derived neurotrophic factor (BDNF) selectively enhanced sensory neurite outgrowth of DRG neurons and motor neurite outgrowth from spinal cord slices respectively. For in vivo studies, the rat sciatic nerve was transected and repaired with a silicone tube filled with a collagen and laminin matrix with NGF/NT3 encapsulated in poly(lactic-co-glycolic acid) (PLGA) microspheres (MP) (LM + MP.NGF/NT3), or a collagen and fibronectin matrix with BDNF in PLGA MPs (FN + MP.BDNF). Retrograde labeling and functional tests showed that LM + MP.NGF/NT3 increased the number of regenerated sensory neurons and improved sensory functional recovery, whereas FN + MP.BDNF preferentially increased regenerated motoneurons and enhanced motor functional recovery. Therefore, combination of ECM molecules with NTFs may be a good approach to selectively enhance motor and sensory axons regeneration and promote appropriate target reinnervation.

  16. Uncovering sensory axonal dysfunction in asymptomatic type 2 diabetic neuropathy

    PubMed Central

    Sung, Jia-Ying; Tani, Jowy; Chang, Tsui-San; Lin, Cindy Shin-Yi

    2017-01-01

    This study investigated sensory and motor nerve excitability properties to elucidate the development of diabetic neuropathy. A total of 109 type 2 diabetes patients were recruited, and 106 were analyzed. According to neuropathy severity, patients were categorized into G0, G1, and G2+3 groups using the total neuropathy score-reduced (TNSr). Patients in the G0 group were asymptomatic and had a TNSr score of 0. Sensory and motor nerve excitability data from diabetic patients were compared with data from 33 healthy controls. Clinical assessment, nerve conduction studies, and sensory and motor nerve excitability testing data were analyzed to determine axonal dysfunction in diabetic neuropathy. In the G0 group, sensory excitability testing revealed increased stimulus for the 50% sensory nerve action potential (P<0.05), shortened strength-duration time constant (P<0.01), increased superexcitability (P<0.01), decreased subexcitability (P<0.05), decreased accommodation to depolarizing current (P<0.01), and a trend of decreased accommodation to hyperpolarizing current in threshold electrotonus. All the changes progressed into G1 (TNSr 1–8) and G2+3 (TNSr 9–24) groups. In contrast, motor excitability only had significantly increased stimulus for the 50% compound motor nerve action potential (P<0.01) in the G0 group. This study revealed that the development of axonal dysfunction in sensory axons occurred prior to and in a different fashion from motor axons. Additionally, sensory nerve excitability tests can detect axonal dysfunction even in asymptomatic patients. These insights further our understanding of diabetic neuropathy and enable the early detection of sensory axonal abnormalities, which may provide a basis for neuroprotective therapeutic approaches. PMID:28182728

  17. Uncovering sensory axonal dysfunction in asymptomatic type 2 diabetic neuropathy.

    PubMed

    Sung, Jia-Ying; Tani, Jowy; Chang, Tsui-San; Lin, Cindy Shin-Yi

    2017-01-01

    This study investigated sensory and motor nerve excitability properties to elucidate the development of diabetic neuropathy. A total of 109 type 2 diabetes patients were recruited, and 106 were analyzed. According to neuropathy severity, patients were categorized into G0, G1, and G2+3 groups using the total neuropathy score-reduced (TNSr). Patients in the G0 group were asymptomatic and had a TNSr score of 0. Sensory and motor nerve excitability data from diabetic patients were compared with data from 33 healthy controls. Clinical assessment, nerve conduction studies, and sensory and motor nerve excitability testing data were analyzed to determine axonal dysfunction in diabetic neuropathy. In the G0 group, sensory excitability testing revealed increased stimulus for the 50% sensory nerve action potential (P<0.05), shortened strength-duration time constant (P<0.01), increased superexcitability (P<0.01), decreased subexcitability (P<0.05), decreased accommodation to depolarizing current (P<0.01), and a trend of decreased accommodation to hyperpolarizing current in threshold electrotonus. All the changes progressed into G1 (TNSr 1-8) and G2+3 (TNSr 9-24) groups. In contrast, motor excitability only had significantly increased stimulus for the 50% compound motor nerve action potential (P<0.01) in the G0 group. This study revealed that the development of axonal dysfunction in sensory axons occurred prior to and in a different fashion from motor axons. Additionally, sensory nerve excitability tests can detect axonal dysfunction even in asymptomatic patients. These insights further our understanding of diabetic neuropathy and enable the early detection of sensory axonal abnormalities, which may provide a basis for neuroprotective therapeutic approaches.

  18. Topographically specific regeneration of sensory axons in the spinal cord.

    PubMed

    Harvey, Pamela; Gong, Bangjian; Rossomando, Anthony J; Frank, Eric

    2010-06-22

    Artemin, a member of the glial-derived neurotrophic factor family, promotes robust regeneration of sensory axons after dorsal root crush. We report here that several classes of sensory axons regenerate to topographically appropriate regions of the dorsal horn with artemin treatment. Projections of regenerated muscle and cutaneous myelinated sensory afferents are restricted to the correct spinal segments and to appropriate regions within spinal gray matter. Regenerated unmyelinated axons expressing calcitonin gene-related peptide project only to superficial laminae of the dorsal horn, where uninjured nociceptive afferents project normally. In contrast, intraventricular infusion of a soluble form of the Nogo receptor that blocks the action of several myelin-associated inhibitory proteins promotes relatively unrestricted regeneration of sensory axons throughout the dorsal white and gray matter of the spinal cord. These results demonstrate that cues capable of guiding regenerating axons to appropriate spinal targets persist in the adult mammalian cord, but only some methods of stimulating regeneration allow the use of these cues by growing axons.

  19. Reversible Axonal Dystrophy by Calcium Modulation in Frataxin-Deficient Sensory Neurons of YG8R Mice.

    PubMed

    Mollá, Belén; Muñoz-Lasso, Diana C; Riveiro, Fátima; Bolinches-Amorós, Arantxa; Pallardó, Federico V; Fernandez-Vilata, Angel; de la Iglesia-Vaya, María; Palau, Francesc; Gonzalez-Cabo, Pilar

    2017-01-01

    Friedreich's ataxia (FRDA) is a peripheral neuropathy involving a loss of proprioceptive sensory neurons. Studies of biopsies from patients suggest that axonal dysfunction precedes the death of proprioceptive neurons in a dying-back process. We observed that the deficiency of frataxin in sensory neurons of dorsal root ganglia (DRG) of the YG8R mouse model causes the formation of axonal spheroids which retain dysfunctional mitochondria, shows alterations in the cytoskeleton and it produces impairment of axonal transport and autophagic flux. The homogenous distribution of axonal spheroids along the neurites supports the existence of continues focal damages. This lead us to propose for FRDA a model of distal axonopathy based on axonal focal damages. In addition, we observed the involvement of oxidative stress and dyshomeostasis of calcium in axonal spheroid formation generating axonal injury as a primary cause of pathophysiology. Axonal spheroids may be a consequence of calcium imbalance, thus we propose the quenching or removal extracellular Ca(2+) to prevent spheroids formation. In our neuronal model, treatments with BAPTA and o-phenanthroline reverted the axonal dystrophy and the mitochondrial dysmorphic parameters. These results support the hypothesis that axonal pathology is reversible in FRDA by pharmacological manipulation of intracellular Ca(2+) with Ca(2+) chelators or metalloprotease inhibitors, preventing Ca(2+)-mediated axonal injury. Thus, the modulation of Ca(2+) levels may be a relevant therapeutic target to develop early axonal protection and prevent dying-back neurodegeneration.

  20. Sodium Channels, Mitochondria, and Axonal Degeneration in Peripheral Neuropathy.

    PubMed

    Persson, Anna-Karin; Hoeijmakers, Janneke G J; Estacion, Mark; Black, Joel A; Waxman, Stephen G

    2016-05-01

    Peripheral neuropathy results from damage to peripheral nerves and is often accompanied by pain in affected limbs. Treatment represents an unmet medical need and a thorough understanding of the mechanisms underlying axonal injury is needed. Longer nerve fibers tend to degenerate first (length-dependence), and patients carrying pathogenic mutations throughout life usually become symptomatic in mid- or late-life (time-dependence). The activity of voltage-gated sodium channels can contribute to axonal injury and sodium channel gain-of-function mutations have been linked to peripheral neuropathy. Recent studies have implicated sodium channel activity, mitochondrial compromise, and reverse-mode Na(+)/Ca(2+) exchange in time- and length-dependent axonal injury. Elucidation of molecular mechanisms underlying axonal injury in peripheral neuropathy may provide new therapeutic strategies for this painful and debilitating condition.

  1. Calsyntenin-1 Regulates Axon Branching and Endosomal Trafficking during Sensory Neuron Development In Vivo

    PubMed Central

    Ponomareva, Olga Y.; Holmen, Ian C.; Sperry, Aiden J.; Eliceiri, Kevin W.

    2014-01-01

    Precise regulation of axon branching is crucial for neuronal circuit formation, yet the mechanisms that control branch formation are not well understood. Moreover, the highly complex morphology of neurons makes them critically dependent on protein/membrane trafficking and transport systems, although the functions for membrane trafficking in neuronal morphogenesis are largely undefined. Here we identify a kinesin adaptor, Calsyntenin-1 (Clstn-1), as an essential regulator of axon branching and neuronal compartmentalization in vivo. We use morpholino knockdown and a Clstn-1 mutant to show that Clstn-1 is required for formation of peripheral but not central sensory axons, and for peripheral axon branching in zebrafish. We used live imaging of endosomal trafficking in vivo to show that Clstn-1 regulates transport of Rab5-containing endosomes from the cell body to specific locations of developing axons. Our results suggest a model in which Clstn-1 patterns separate axonal compartments and define their ability to branch by directing trafficking of specific endosomes. PMID:25009257

  2. Differential protection of neuromuscular sensory and motor axons and their endings in Wld(S) mutant mice.

    PubMed

    Oyebode, O R O; Hartley, R; Singhota, J; Thomson, D; Ribchester, R R

    2012-01-03

    Orthograde Wallerian degeneration normally brings about fragmentation of peripheral nerve axons and their sensory or motor endings within 24-48 h in mice. However, neuronal expression of the chimaeric, Wld(S) gene mutation extends survival of functioning axons and their distal endings for up to 3 weeks after nerve section. Here we studied the pattern and rate of degeneration of sensory axons and their annulospiral endings in deep lumbrical muscles of Wld(S) mice, and compared these with motor axons and their terminals, using neurone-specific transgenic expression of the fluorescent proteins yellow fluorescent protein (YFP) or cyan fluorescent protein (CFP) as morphological reporters. Surprisingly, sensory endings were preserved for up to 20 days, at least twice as long as the most resilient motor nerve terminals. Protection of sensory endings and axons was also much less sensitive to Wld(S) gene-copy number or age than motor axons and their endings. Protection of γ-motor axons and their terminals innervating the juxtaequatorial and polar regions of the spindles was less than sensory axons but greater than α-motor axons. The differences between sensory and motor axon protection persisted in electrically silent, organotypic nerve-explant cultures suggesting that residual axonal activity does not contribute to the sensory-motor axon differences in vivo. Quantitative, Wld(S)-specific immunostaining of dorsal root ganglion (DRG) neurones and motor neurones in homozygous Wld(S) mice suggested that the nuclei of large DRG neurones contain about 2.4 times as much Wld(S) protein as motor neurones. By contrast, nuclear fluorescence of DRG neurones in homozygotes was only 1.5 times brighter than in heterozygotes stained under identical conditions. Thus, differences in axonal or synaptic protection within the same Wld(S) mouse may most simply be explained by differences in expression level of Wld(S) protein between neurones. Mimicry of Wld(S)-induced protection may also have

  3. Local erythropoietin signaling enhances regeneration in peripheral axons.

    PubMed

    Toth, C; Martinez, J A; Liu, W Q; Diggle, J; Guo, G F; Ramji, N; Mi, R; Hoke, A; Zochodne, D W

    2008-06-23

    Erythropoietin (EPO) and its receptor (EPO-R), mediate neuroprotection from axonopathy and apoptosis in the peripheral nervous system (PNS). We examined the impact and potential mechanisms of local EPO signaling on regenerating PNS axons in vivo and in vitro. As a consequence of injury, peripheral nerve axons and DRG neurons have a marked increase in the expression of EPO and EPO-R. Local delivery of EPO via conduit over 2 weeks to rat sciatic nerve following crush injury increased the density and maturity of regenerating myelinated axons growing distally from the crush site. In addition, EPO also rescued retrograde degeneration and atrophy of axons. EPO substantially increased the density and intensity of calcitonin gene-related peptide (CGRP) expression within outgrowing axons. Behavioral improvements in sensorimotor function also occurred in rats exposed to near nerve EPO delivery. EPO delivery led to decreased nuclear factor kappaB (NFkB) activation but increased phosphorylation of Akt and STAT3 within nerve and dorsal root ganglia neurons indicating rescue from an injury phenotype. Spinal cord explant studies also demonstrated a similar dose-dependent effect of EPO upon motor axonal outgrowth. Local EPO signaling enhances regenerating peripheral nervous system axons in addition to its known neuroprotection. Exogenous EPO may have a therapeutic role in a large number of peripheral nerve diseases through its impact on regeneration.

  4. c-Jun activation in Schwann cells protects against loss of sensory axons in inherited neuropathy

    PubMed Central

    Hantke, Janina; Carty, Lucy; Wagstaff, Laura J.; Turmaine, Mark; Wilton, Daniel K.; Quintes, Susanne; Koltzenburg, Martin; Baas, Frank; Mirsky, Rhona

    2014-01-01

    Charcot–Marie–Tooth disease type 1A is the most frequent inherited peripheral neuropathy. It is generally due to heterozygous inheritance of a partial chromosomal duplication resulting in over-expression of PMP22. A key feature of Charcot–Marie–Tooth disease type 1A is secondary death of axons. Prevention of axonal loss is therefore an important target of clinical intervention. We have previously identified a signalling mechanism that promotes axon survival and prevents neuron death in mechanically injured peripheral nerves. This work suggested that Schwann cells respond to injury by activating/enhancing trophic support for axons through a mechanism that depends on upregulation of the transcription factor c-Jun in Schwann cells, resulting in the sparing of axons that would otherwise die. As c-Jun orchestrates Schwann cell support for distressed neurons after mechanical injury, we have now asked: do Schwann cells also activate a c-Jun dependent neuron-supportive programme in inherited demyelinating disease? We tested this by using the C3 mouse model of Charcot–Marie–Tooth disease type 1A. In line with our previous findings in humans with Charcot–Marie–Tooth disease type 1A, we found that Schwann cell c-Jun was elevated in (uninjured) nerves of C3 mice. We determined the impact of this c-Jun activation by comparing C3 mice with double mutant mice, namely C3 mice in which c-Jun had been conditionally inactivated in Schwann cells (C3/Schwann cell-c-Jun−/− mice), using sensory-motor tests and electrophysiological measurements, and by counting axons in proximal and distal nerves. The results indicate that c-Jun elevation in the Schwann cells of C3 nerves serves to prevent loss of myelinated sensory axons, particularly in distal nerves, improve behavioural symptoms, and preserve F-wave persistence. This suggests that Schwann cells have two contrasting functions in Charcot–Marie–Tooth disease type 1A: on the one hand they are the genetic source of

  5. Inflections in threshold electrotonus to depolarizing currents in sensory axons.

    PubMed

    Burke, David; Howells, James; Trevillion, Louise; Kiernan, Matthew C; Bostock, Hugh

    2007-12-01

    Threshold electrotonus involves tracking the changes in axonal excitability produced by subthreshold polarizing currents and is the only technique that allows insight into the function of internodal conductances in human subjects in vivo. There is often an abrupt transient reversal of the threshold change as excitability increases in response to conditioning depolarizing currents (S1 phase). In recordings from motor axons, it has been recently demonstrated that this notch or inflection is due to activation of low-threshold axons. We report that a notch is frequently seen in sensory recordings (in 33 of 50 healthy subjects) using the standard threshold electrotonus protocol. When large, the notch can distort subsequent phases of threshold electrotonus and could complicate quantitative measurements and modeling studies.

  6. Human Embryonic Stem Cell-Derived Progenitors Assist Functional Sensory Axon Regeneration after Dorsal Root Avulsion Injury

    PubMed Central

    Hoeber, Jan; Trolle, Carl; Konig, Niclas; Du, Zhongwei; Gallo, Alessandro; Hermans, Emmanuel; Aldskogius, Hakan; Shortland, Peter; Zhang, Su-Chun; Deumens, Ronald; Kozlova, Elena N.

    2015-01-01

    Dorsal root avulsion results in permanent impairment of sensory functions due to disconnection between the peripheral and central nervous system. Improved strategies are therefore needed to reconnect injured sensory neurons with their spinal cord targets in order to achieve functional repair after brachial and lumbosacral plexus avulsion injuries. Here, we show that sensory functions can be restored in the adult mouse if avulsed sensory fibers are bridged with the spinal cord by human neural progenitor (hNP) transplants. Responses to peripheral mechanical sensory stimulation were significantly improved in transplanted animals. Transganglionic tracing showed host sensory axons only in the spinal cord dorsal horn of treated animals. Immunohistochemical analysis confirmed that sensory fibers had grown through the bridge and showed robust survival and differentiation of the transplants. Section of the repaired dorsal roots distal to the transplant completely abolished the behavioral improvement. This demonstrates that hNP transplants promote recovery of sensorimotor functions after dorsal root avulsion, and that these effects are mediated by spinal ingrowth of host sensory axons. These results provide a rationale for the development of novel stem cell-based strategies for functionally useful bridging of the peripheral and central nervous system. PMID:26053681

  7. Npn-1 contributes to axon-axon interactions that differentially control sensory and motor innervation of the limb.

    PubMed

    Huettl, Rosa-Eva; Soellner, Heidi; Bianchi, Elisa; Novitch, Bennett G; Huber, Andrea B

    2011-02-01

    The initiation, execution, and completion of complex locomotor behaviors are depending on precisely integrated neural circuitries consisting of motor pathways that activate muscles in the extremities and sensory afferents that deliver feedback to motoneurons. These projections form in tight temporal and spatial vicinities during development, yet the molecular mechanisms and cues coordinating these processes are not well understood. Using cell-type specific ablation of the axon guidance receptor Neuropilin-1 (Npn-1) in spinal motoneurons or in sensory neurons in the dorsal root ganglia (DRG), we have explored the contribution of this signaling pathway to correct innervation of the limb. We show that Npn-1 controls the fasciculation of both projections and mediates inter-axonal communication. Removal of Npn-1 from sensory neurons results in defasciculation of sensory axons and, surprisingly, also of motor axons. In addition, the tight coupling between these two heterotypic axonal populations is lifted with sensory fibers now leading the spinal nerve projection. These findings are corroborated by partial genetic elimination of sensory neurons, which causes defasciculation of motor projections to the limb. Deletion of Npn-1 from motoneurons leads to severe defasciculation of motor axons in the distal limb and dorsal-ventral pathfinding errors, while outgrowth and fasciculation of sensory trajectories into the limb remain unaffected. Genetic elimination of motoneurons, however, revealed that sensory axons need only minimal scaffolding by motor axons to establish their projections in the distal limb. Thus, motor and sensory axons are mutually dependent on each other for the generation of their trajectories and interact in part through Npn-1-mediated fasciculation before and within the plexus region of the limbs.

  8. Npn-1 Contributes to Axon-Axon Interactions That Differentially Control Sensory and Motor Innervation of the Limb

    PubMed Central

    Bianchi, Elisa; Novitch, Bennett G.; Huber, Andrea B.

    2011-01-01

    The initiation, execution, and completion of complex locomotor behaviors are depending on precisely integrated neural circuitries consisting of motor pathways that activate muscles in the extremities and sensory afferents that deliver feedback to motoneurons. These projections form in tight temporal and spatial vicinities during development, yet the molecular mechanisms and cues coordinating these processes are not well understood. Using cell-type specific ablation of the axon guidance receptor Neuropilin-1 (Npn-1) in spinal motoneurons or in sensory neurons in the dorsal root ganglia (DRG), we have explored the contribution of this signaling pathway to correct innervation of the limb. We show that Npn-1 controls the fasciculation of both projections and mediates inter-axonal communication. Removal of Npn-1 from sensory neurons results in defasciculation of sensory axons and, surprisingly, also of motor axons. In addition, the tight coupling between these two heterotypic axonal populations is lifted with sensory fibers now leading the spinal nerve projection. These findings are corroborated by partial genetic elimination of sensory neurons, which causes defasciculation of motor projections to the limb. Deletion of Npn-1 from motoneurons leads to severe defasciculation of motor axons in the distal limb and dorsal-ventral pathfinding errors, while outgrowth and fasciculation of sensory trajectories into the limb remain unaffected. Genetic elimination of motoneurons, however, revealed that sensory axons need only minimal scaffolding by motor axons to establish their projections in the distal limb. Thus, motor and sensory axons are mutually dependent on each other for the generation of their trajectories and interact in part through Npn-1-mediated fasciculation before and within the plexus region of the limbs. PMID:21364975

  9. Ankyrin-B structurally defines terminal microdomains of peripheral somatosensory axons.

    PubMed

    Engelhardt, Maren; Vorwald, Silke; Sobotzik, Jürgen-Markus; Bennett, Vann; Schultz, Christian

    2013-07-01

    Axons are subdivided into functionally organized microdomains, which are required for generation and propagation of action potentials (APs). In the central nervous system (CNS), APs are generated near the soma in the axon initial segment (AIS) and propagated by nodes of Ranvier (noR). The crucial role of the membrane adapter proteins ankyrin-B and ankyrin-G as organizers of AIS and noR is now well established. By comparison, little is known on the localization and function of these proteins in sensory axon terminals of the peripheral nervous systems (PNS). Here, we tested the hypothesis that somatosensory PNS terminals are organized by distinct members of the ankyrin protein family. We discovered a specific distribution of ankyrin-B in somatosensory axon terminals of skin and muscle. Specifically, ankyrin-B was localized along the membrane of axons innervating Meissner corpuscles, Pacinian corpuscles and hair follicle receptors. Likewise, proprioceptive terminals of muscle spindles exhibited prominent ankyrin-B expression. Furthermore, ankyrin-B expression extended into nociceptive and thermoceptive intraepidermal nerve fibers. Interestingly, all studied somatosensory terminals were largely devoid of ankyrin-G, indicating that this scaffolding protein does not contribute to organization of mechanoelectric transduction zones in peripheral somatosensory neurons. Instead, we propose that ankyrin-B serves as a major membrane organizer in mechanoreceptive and nociceptive terminals of the PNS.

  10. Comparing excitability at 37°C versus at 20°C: Differences between motor and sensory axons.

    PubMed

    Kovalchuk, Maria O; Franssen, Hessel; Van Schelven, Leonard J; Sleutjes, Boudewijn T H M

    2017-09-06

    In some peripheral nervous system disorders, cold induces symptoms of muscle weakness without loss of sensation. To understand this selective effect on motor function, it is first essential to delineate the effects of cooling in motor and sensory axons of healthy subjects. In 17 healthy volunteers, we performed excitability and clinical tests of median nerve motor and sensory axons at 37°C and at 20°C. Clinical tests consisted of assessing thenar muscle strength, 2-point discrimination, and joint position sense of the third finger. Excitability tests showed that cooling induced opposite changes to hyperpolarizing current in threshold electrotonus (motor, decreased threshold change; sensory, increased threshold change) and current-voltage relation slopes (motor, steepening; sensory, less steep). Clinical tests showed worsening in motor function but no consistent changes in sensory function. Cooling induces changes in motor axons consistent with depolarization and more complicated changes in sensory axons, possibly related to differences in hyperpolarization-activated cyclic nucleotide-gated channel expression. Muscle Nerve, 2017. © 2017 Wiley Periodicals, Inc.

  11. An apolipoprotein E-mimetic stimulates axonal regeneration and remyelination after peripheral nerve injury.

    PubMed

    Li, Feng-Qiao; Fowler, Kenneth A; Neil, Jessica E; Colton, Carol A; Vitek, Michael P

    2010-07-01

    Elevated apolipoprotein E (apoE) synthesis within crushed sciatic nerves advocates that apoE could benefit axonal repair and reconstruction of axonal and myelin membranes. We created an apoE-mimetic peptide, COG112 (acetyl-RQIKIWFQNRRMKWKKCLRVRLASHLRKLRKRLL-amide), and found that postinjury treatment with COG112 significantly improved recovery of motor and sensory function following sciatic nerve crush in C57BL/6 mice. Morphometric analysis of injured sciatic nerves revealed that COG112 promoted axonal regrowth after 2 weeks of treatment. More strikingly, the thickness of myelin sheaths was increased by COG112 treatment. Consistent with these histological findings, COG112 potently elevated growth associated protein 43 (GAP-43) and peripheral myelin protein zero (P0), which are markers of axon regeneration and remyelination, respectively. Electron microscopic examination further suggested that the apoE-mimetic COG112 may increase clearance of myelin debris. Schwann cell uptake of cholesterol-containing low-density lipoprotein particles was selectively enhanced by COG112 treatment in a Schwann cell line S16. Moreover, COG112 significantly promoted axon elongation in primary dorsal root ganglion cultures from rat pups. Considering that cholesterol and lipids are needed for reconstructing myelin sheaths and axon extension, these data support a hypothesis where supplementation with exogenous apoE-mimetics such as COG112 may be a promising strategy for restoring lost functional and structural elements following nerve injury.

  12. An Apolipoprotein E-Mimetic Stimulates Axonal Regeneration and Remyelination after Peripheral Nerve Injury

    PubMed Central

    Fowler, Kenneth A.; Neil, Jessica E.; Colton, Carol A.; Vitek, Michael P.

    2010-01-01

    Elevated apolipoprotein E (apoE) synthesis within crushed sciatic nerves advocates that apoE could benefit axonal repair and reconstruction of axonal and myelin membranes. We created an apoE-mimetic peptide, COG112 (acetyl-RQIKIWFQNRRMKWKKCLRVRLASHLRKLRKRLL-amide), and found that postinjury treatment with COG112 significantly improved recovery of motor and sensory function following sciatic nerve crush in C57BL/6 mice. Morphometric analysis of injured sciatic nerves revealed that COG112 promoted axonal regrowth after 2 weeks of treatment. More strikingly, the thickness of myelin sheaths was increased by COG112 treatment. Consistent with these histological findings, COG112 potently elevated growth associated protein 43 (GAP-43) and peripheral myelin protein zero (P0), which are markers of axon regeneration and remyelination, respectively. Electron microscopic examination further suggested that the apoE-mimetic COG112 may increase clearance of myelin debris. Schwann cell uptake of cholesterol-containing low-density lipoprotein particles was selectively enhanced by COG112 treatment in a Schwann cell line S16. Moreover, COG112 significantly promoted axon elongation in primary dorsal root ganglion cultures from rat pups. Considering that cholesterol and lipids are needed for reconstructing myelin sheaths and axon extension, these data support a hypothesis where supplementation with exogenous apoE-mimetics such as COG112 may be a promising strategy for restoring lost functional and structural elements following nerve injury. PMID:20406857

  13. Peripheral nerve: from the microscopic functional unit of the axon to the biomechanically loaded macroscopic structure.

    PubMed

    Topp, Kimberly S; Boyd, Benjamin S

    2012-01-01

    Peripheral nerves are composed of motor and sensory axons, associated ensheathing Schwann cells, and organized layers of connective tissues that are in continuity with the tissues of the central nervous system. Nerve fiber anatomy facilitates conduction of electrical impulses to convey information over a distance, and the length of these polarized cells necessitates regulated axonal transport of organelles and structural proteins for normal cell function. Nerve connective tissues serve a protective function as the limb is subjected to the stresses of myriad limb positions and postures. Thus, the tissues are uniquely arranged to control the local nerve fiber environment and modulate physical stresses. In this brief review, we describe the microscopic anatomy and physiology of peripheral nerve and the biomechanical properties that enable nerve to withstand the physical stresses of everyday life. Copyright © 2012 Hanley & Belfus. Published by Elsevier Inc. All rights reserved.

  14. Mechanisms of Distal Axonal Degeneration in Peripheral Neuropathies

    PubMed Central

    Cashman, Christopher R.; Höke, Ahmet

    2015-01-01

    Peripheral neuropathy is a common complication of a variety of diseases and treatments, including diabetes, cancer chemotherapy, and infectious causes (HIV, hepatitis C, and Campylobacter jejuni). Despite the fundamental difference between these insults, peripheral neuropathy develops as a combination of just six primary mechanisms: altered metabolism, covalent modification, altered organelle function and reactive oxygen species formation, altered intracellular and inflammatory signaling, slowed axonal transport, and altered ion channel dynamics and expression. All of these pathways converge to lead to axon dysfunction and symptoms of neuropathy. The detailed mechanisms of axon degeneration itself have begun to be elucidated with studies of animal models with altered degeneration kinetics, including the slowed Wallerian degeneration (Wlds) and Sarmknockout animal models. These studies have shown axonal degeneration to occur througha programmed pathway of injury signaling and cytoskeletal degradation. Insights into the common disease insults that converge on the axonal degeneration pathway promise to facilitate the development of therapeutics that may be effective against other mechanisms of neurodegeneration. PMID:25617478

  15. Schwann cell mitochondria as key regulators in the development and maintenance of peripheral nerve axons.

    PubMed

    Ino, Daisuke; Iino, Masamitsu

    2017-03-01

    Formation of myelin sheaths by Schwann cells (SCs) enables rapid and efficient transmission of action potentials in peripheral axons, and disruption of myelination results in disorders that involve decreased sensory and motor functions. Given that construction of SC myelin requires high levels of lipid and protein synthesis, mitochondria, which are pivotal in cellular metabolism, may be potential regulators of the formation and maintenance of SC myelin. Supporting this notion, abnormal mitochondria are found in SCs of neuropathic peripheral nerves in both human patients and the relevant animal models. However, evidence for the importance of SC mitochondria in myelination has been limited, until recently. Several studies have recently used genetic approaches that allow SC-specific ablation of mitochondrial metabolic activity in living animals to show the critical roles of SC mitochondria in the development and maintenance of peripheral nerve axons. Here, we review current knowledge about the involvement of SC mitochondria in the formation and dysfunction of myelinated axons in the peripheral nervous system.

  16. Phenotyping the Function of TRPV1-Expressing Sensory Neurons by Targeted Axonal Silencing

    PubMed Central

    Brenneis, Christian; Kistner, Katrin; Puopolo, Michelino; Segal, David; Roberson, David; Sisignano, Marco; Labocha, Sandra; Ferreirós, Nerea; Strominger, Amanda; Cobos, Enrique J.; Ghasemlou, Nader; Geisslinger, Gerd; Reeh, Peter W.; Bean, Bruce P.; Woolf, Clifford J.

    2013-01-01

    Specific somatosensations may be processed by different subsets of primary afferents. C-fibers expressing heat-sensitive TRPV1 channels are proposed, for example, to be heat but not mechanical pain detectors. To phenotype in rats the sensory function of TRPV1+ afferents, we rapidly and selectively silenced only their activity, by introducing the membrane-impermeant sodium channel blocker QX-314 into these axons via the TRPV1 channel pore. Using tandem mass spectrometry we show that upon activation with capsaicin, QX-314 selectively accumulates in the cytosol only of TRPV1-expressing cells, and not in control cells. Exposure to QX-314 and capsaicin induces in small DRG neurons a robust sodium current block within 30 s. In sciatic nerves, application of extracellular QX-314 with capsaicin persistently reduces C-fiber but not A-fiber compound action potentials and this effect does not occur in TRPV1−/− mice. Behavioral phenotyping after selectively silencing TRPV1+ sciatic nerve axons by perineural injections of QX-314 and capsaicin reveals deficits in heat and mechanical pressure but not pinprick or light touch perception. The response to intraplantar capsaicin is substantially reduced, as expected. During inflammation, silencing TRPV1+ axons abolishes heat, mechanical, and cold hyperalgesia but tactile and cold allodynia remain following peripheral nerve injury. These results indicate that TRPV1-expressing sensory neurons process particular thermal and mechanical somatosensations, and that the sensory channels activated by mechanical and cold stimuli to produce pain in naive/inflamed rats differ from those in animals after peripheral nerve injury. PMID:23283344

  17. Responses of human sensory and motor axons to the release of ischaemia and to hyperpolarizing currents.

    PubMed

    Lin, Cindy S-Y; Kuwabara, Satoshi; Cappelen-Smith, Cecilia; Burke, David

    2002-06-15

    This study compared directly the post-ischaemic behaviour of sensory and motor axons in the human median nerve, focusing on the excitability changes produced by ischaemia and its release and by continuous polarizing DC. The decrease in threshold during ischaemia for 13 min was greater, the post-ischaemic increase in threshold was more rapid, and the return to the pre-ischaemic excitability took longer in sensory axons. However, a transient depolarizing threshold shift developed in sensory axons a few minutes after release of ischaemia. This pattern could not be reproduced by polarizing currents designed to mimic the probable pump-induced changes in membrane potential, even though the applied currents produced greater changes in threshold. Hyperpolarizing currents of equivalent intensity produced a greater increase in threshold for motor axons than sensory axons and, in studies of threshold electrotonus using graded hyperpolarizing DC, accommodation was greater in sensory than motor axons. The post-ischaemic changes in threshold were not uniform for axons of different threshold, whether sensory or motor, the threshold increase was usually less prominent for low-threshold axons. A transient post-ischaemic depolarization could be produced in motor axons with ischaemia of 20 min duration. Greater ischaemic and post-ischaemic changes in threshold for sensory axons could reflect greater dependence on the electrogenic Na+-K+ pump to maintain resting membrane potential and/or greater extracellular K+ accumulation in ischaemic sensory axons. Inward K+ currents due to extracellular K+ accumulation would then be more likely to trigger a depolarizing shift in membrane potential, the degree of K+ accumulation and pump activity being dependent on the duration of ischaemia. In sensory axons the greater tendency to accommodate to hyperpolarizing stimuli presumably contributes to shaping their post-ischaemic behaviour but is probably insufficient to explain why their behaviour

  18. Spatiotemporal gradients of intra-axonal [Na+] after transection and resealing in lizard peripheral myelinated axons.

    PubMed Central

    David, G; Barrett, J N; Barrett, E F

    1997-01-01

    1. Post-transection changes in intracellular Na+ ([Na+]i) were measured in lizard peripheral axons ionophoretically injected with the Na(+)-sensitive ratiometric dye, sodium-binding benzofuran isophthalate (SBFI). 2. Following axonal transection in physiological saline [Na+]i increased to more than 100 mM in a region that quickly extended hundreds of micrometers from the transection site. This post-transection increase in [Na+]i was similar when the bath contained 5 microM tetrodotoxin, but was absent in Na(+)-free solution. Depolarization of uncut axons in 50 mM K+ produced little or no elevation of [Na+]i until veratridine was added. These results suggest that the post-transection increase in [Na+]i was due mainly to Na+ entry via the cut end, rather than via depolarization-activated Na+ channels. 3. The spatiotemporal profile of the post-transection increase in [Na+]i could be accounted for by movement of Na+ from the cut end with an apparent diffusion coefficient of 1.3 x 10(-5) cm2 s-1. 4. [Na+]i began to decline toward resting levels by 20 +/- 15 min (mean +/- S.D.) post-transection, except in regions of the axon within 160 +/- 85 microns of the transection site, where [Na+]i remained high. The boundary between axonal regions in which [Na+]i did or did not recover probably defines a locus of resealing of the axonal membrane. 5. [Na+]i returned to resting values within about 1 h after resealing, even in axonal regions where the normal transmembrane [Na+] gradient had completely dissipated. The recovery of [Na+]i was faster and reached lower levels than expected by diffusional redistribution of Na+ along the axon. Partial recovery occurred even in an isolated internode, indicating that the internodal axolemma can actively extrude Na+. Images Figure 2 Figure 4 Figure 6 PMID:9032679

  19. The core planar cell polarity gene prickle interacts with flamingo to promote sensory axon advance in the Drosophila embryo.

    PubMed

    Mrkusich, Eli M; Flanagan, Dustin J; Whitington, Paul M

    2011-10-01

    The atypical cadherin Drosophila protein Flamingo and its vertebrate homologues play widespread roles in the regulation of both dendrite and axon growth. However, little is understood about the molecular mechanisms that underpin these functions. Whereas flamingo interacts with a well-defined group of genes in regulating planar cell polarity, previous studies have uncovered little evidence that the other core planar cell polarity genes are involved in regulation of neurite growth. We present data in this study showing that the planar cell polarity gene prickle interacts with flamingo in regulating sensory axon advance at a key choice point - the transition between the peripheral nervous system and the central nervous system. The cytoplasmic tail of the Flamingo protein is not required for this interaction. Overexpression of another core planar cell polarity gene dishevelled produces a similar phenotype to prickle mutants, suggesting that this gene may also play a role in regulation of sensory axon advance.

  20. Skin incision induces expression of axonal regeneration-related genes in adult rat spinal sensory neurons

    PubMed Central

    Hill, Caitlin E.; Harrison, Benjamin J.; Rau, Kris K.; Hougland, M. Tyler; Bunge, Mary Bartlett; Mendell, Lorne M.; Petruska, Jeffrey C.

    2010-01-01

    Skin incision and nerve injury both induce painful conditions. Incisional and post-surgical pain is believed to arise primarily from inflammation of tissue and the subsequent sensitization of peripheral and central neurons. The role of axonal regeneration-related processes in development of pain has only been considered when there has been injury to the peripheral nerve itself, even though tissue damage likely induces injury of resident axons. We sought to determine if skin incision would affect expression of regeneration-related genes such as activating transcription factor 3 (ATF3) in dorsal root ganglion (DRG) neurons. ATF3 is absent from DRG neurons of the normal adult rodent, but is induced by injury of peripheral nerves and modulates the regenerative capacity of axons. Image analysis of immunolabeled DRG sections revealed that skin incision led to an increase in the number of DRG neurons expressing ATF3. RT-PCR indicated that other regeneration-associated genes (galanin, GAP-43, Gadd45a) were also increased, further suggesting an injury-like response in DRG neurons. Our finding that injury of skin can induce expression of neuronal injury/regeneration-associated genes may impact how clinical post-surgical pain is investigated and treated. Perspective Tissue injury, even without direct nerve injury, may induce a state of enhanced growth capacity in sensory neurons. Axonal regeneration-associated processes should be considered alongside nerve signal conduction and inflammatory/sensitization processes as possible mechanisms contributing to pain, particularly the transition from acute to chronic pain. PMID:20627820

  1. Extrinsic cellular and molecular mediators of peripheral axonal regeneration.

    PubMed

    Bosse, Frank

    2012-07-01

    The ability of injured peripheral nerves to regenerate and reinnervate their original targets is a characteristic feature of the peripheral nervous system (PNS). On the other hand, neurons of the central nervous system (CNS), including retinal ganglion cell (RGC) axons, are incapable of spontaneous regeneration. In the adult PNS, axonal regeneration after injury depends on well-orchestrated cellular and molecular processes that comprise a highly reproducible series of degenerative reactions distal to the site of injury. During this fine-tuned process, named Wallerian degeneration, a remodeling of the distal nerve fragment prepares a permissive microenvironment that permits successful axonal regrowth originating from the proximal nerve fragment. Therefore, a multitude of adjusted intrinsic and extrinsic factors are important for surviving neurons, Schwann cells, macrophages and fibroblasts as well as endothelial cells in order to achieve successful regeneration. The aim of this review is to summarize relevant extrinsic cellular and molecular determinants of successful axonal regeneration in rodents that contribute to the regenerative microenvironment of the PNS.

  2. Peripheral Nerve Diffusion Tensor Imaging: Assessment of Axon and Myelin Sheath Integrity.

    PubMed

    Heckel, A; Weiler, M; Xia, A; Ruetters, M; Pham, M; Bendszus, M; Heiland, S; Baeumer, P

    2015-01-01

    To investigate the potential of diffusion tensor imaging (DTI) parameters as in-vivo biomarkers of axon and myelin sheath integrity of the median nerve in the carpal tunnel as validated by correlation with electrophysiology. MRI examinations at 3T including DTI were conducted on wrists in 30 healthy subjects. After manual segmentation of the median nerve quantitative analysis of fractional anisotropy (FA) as well as axial, radial and mean diffusivity (AD, RD, and MD) was carried out. Pairwise Pearson correlations with electrophysiological parameters comprising sensory nerve action potential (SNAP) and compound muscle action potential (CMAP) as markers of axon integrity, and distal motor latency (dml) and sensory nerve conduction velocity (sNCV) as markers of myelin sheath integrity were computed. The significance criterion was set at P=0.05, Bonferroni corrected for multiple comparisons. DTI parameters showed a distinct proximal-to-distal profile with FA, MD, and RD extrema coinciding in the center of the carpal tunnel. AD correlated with CMAP (r=0.50, p=0.04, Bonf. corr.) but not with markers of myelin sheath integrity. RD correlated with sNCV (r=-0.53, p=0.02, Bonf. corr.) but not with markers of axon integrity. FA correlated with dml (r=-0.63, p=0.002, Bonf. corr.) and sNCV (r=0.68, p=0.001, Bonf. corr.) but not with markers of axon integrity. AD reflects axon integrity, while RD (and FA) reflect myelin sheath integrity as validated by correlation with electrophysiology. DTI parameters consistently indicate a slight decrease of structural integrity in the carpal tunnel as a physiological site of median nerve entrapment. DTI is particularly sensitive, since these findings are observed in healthy participants. Our results encourage future studies to evaluate the potential of DTI in differentiating axon from myelin sheath injury in patients with manifest peripheral neuropathies.

  3. Peripheral Nerve Diffusion Tensor Imaging: Assessment of Axon and Myelin Sheath Integrity

    PubMed Central

    Heckel, A.; Weiler, M.; Xia, A.; Ruetters, M.; Pham, M.; Bendszus, M.; Heiland, S.; Baeumer, P.

    2015-01-01

    Purpose To investigate the potential of diffusion tensor imaging (DTI) parameters as in-vivo biomarkers of axon and myelin sheath integrity of the median nerve in the carpal tunnel as validated by correlation with electrophysiology. Methods MRI examinations at 3T including DTI were conducted on wrists in 30 healthy subjects. After manual segmentation of the median nerve quantitative analysis of fractional anisotropy (FA) as well as axial, radial and mean diffusivity (AD, RD, and MD) was carried out. Pairwise Pearson correlations with electrophysiological parameters comprising sensory nerve action potential (SNAP) and compound muscle action potential (CMAP) as markers of axon integrity, and distal motor latency (dml) and sensory nerve conduction velocity (sNCV) as markers of myelin sheath integrity were computed. The significance criterion was set at P=0.05, Bonferroni corrected for multiple comparisons. Results DTI parameters showed a distinct proximal-to-distal profile with FA, MD, and RD extrema coinciding in the center of the carpal tunnel. AD correlated with CMAP (r=0.50, p=0.04, Bonf. corr.) but not with markers of myelin sheath integrity. RD correlated with sNCV (r=-0.53, p=0.02, Bonf. corr.) but not with markers of axon integrity. FA correlated with dml (r=-0.63, p=0.002, Bonf. corr.) and sNCV (r=0.68, p=0.001, Bonf. corr.) but not with markers of axon integrity. Conclusion AD reflects axon integrity, while RD (and FA) reflect myelin sheath integrity as validated by correlation with electrophysiology. DTI parameters consistently indicate a slight decrease of structural integrity in the carpal tunnel as a physiological site of median nerve entrapment. DTI is particularly sensitive, since these findings are observed in healthy participants. Our results encourage future studies to evaluate the potential of DTI in differentiating axon from myelin sheath injury in patients with manifest peripheral neuropathies. PMID:26114630

  4. Transcriptional changes in sensory ganglia associated with primary afferent axon collateral sprouting in spared dermatome model

    PubMed Central

    Harrison, Benjamin J.; Venkat, Gayathri; Hutson, Thomas; Rau, Kristofer K.; Bunge, Mary Bartlett; Mendell, Lorne M.; Gage, Fred H.; Johnson, Richard D.; Hill, Caitlin; Rouchka, Eric C.; Moon, Lawrence; Petruska, Jeffrey C.

    2015-01-01

    Primary afferent collateral sprouting is a process whereby non-injured primary afferent neurons respond to some stimulus and extend new branches from existing axons. Neurons of both the central and peripheral nervous systems undergo this process, which contributes to both adaptive and maladaptive plasticity (e.g., [1], [2], [3], [4], [5], [6], [7], [8], [9]). In the model used here (the “spared dermatome” model), the intact sensory neurons respond to the denervation of adjacent areas of skin by sprouting new axon branches into that adjacent denervated territory. Investigations of gene expression changes associated with collateral sprouting can provide a better understanding of the molecular mechanisms controlling this process. Consequently, it can be used to develop treatments to promote functional recovery for spinal cord injury and other similar conditions. This report includes raw gene expression data files from microarray experiments in order to study the gene regulation in spared sensory ganglia in the initiation (7 days) and maintenance (14 days) phases of the spared dermatome model relative to intact (“naïve”) sensory ganglia. Data has been deposited into GEO (GSE72551). PMID:26697387

  5. c-Jun activation in Schwann cells protects against loss of sensory axons in inherited neuropathy.

    PubMed

    Hantke, Janina; Carty, Lucy; Wagstaff, Laura J; Turmaine, Mark; Wilton, Daniel K; Quintes, Susanne; Koltzenburg, Martin; Baas, Frank; Mirsky, Rhona; Jessen, Kristján R

    2014-11-01

    Charcot-Marie-Tooth disease type 1A is the most frequent inherited peripheral neuropathy. It is generally due to heterozygous inheritance of a partial chromosomal duplication resulting in over-expression of PMP22. A key feature of Charcot-Marie-Tooth disease type 1A is secondary death of axons. Prevention of axonal loss is therefore an important target of clinical intervention. We have previously identified a signalling mechanism that promotes axon survival and prevents neuron death in mechanically injured peripheral nerves. This work suggested that Schwann cells respond to injury by activating/enhancing trophic support for axons through a mechanism that depends on upregulation of the transcription factor c-Jun in Schwann cells, resulting in the sparing of axons that would otherwise die. As c-Jun orchestrates Schwann cell support for distressed neurons after mechanical injury, we have now asked: do Schwann cells also activate a c-Jun dependent neuron-supportive programme in inherited demyelinating disease? We tested this by using the C3 mouse model of Charcot-Marie-Tooth disease type 1A. In line with our previous findings in humans with Charcot-Marie-Tooth disease type 1A, we found that Schwann cell c-Jun was elevated in (uninjured) nerves of C3 mice. We determined the impact of this c-Jun activation by comparing C3 mice with double mutant mice, namely C3 mice in which c-Jun had been conditionally inactivated in Schwann cells (C3/Schwann cell-c-Jun(-/-) mice), using sensory-motor tests and electrophysiological measurements, and by counting axons in proximal and distal nerves. The results indicate that c-Jun elevation in the Schwann cells of C3 nerves serves to prevent loss of myelinated sensory axons, particularly in distal nerves, improve behavioural symptoms, and preserve F-wave persistence. This suggests that Schwann cells have two contrasting functions in Charcot-Marie-Tooth disease type 1A: on the one hand they are the genetic source of the disease, on the

  6. Acupuncture, connective tissue, and peripheral sensory modulation.

    PubMed

    Langevin, Helene M

    2014-01-01

    Although considerable controversy surrounds the legitimacy of acupuncture as a treatment, a growing literature on the physiological effects of acupuncture needling in animals and humans is providing new insights into basic cellular mechanisms including connective tissue mechanotransduction and purinergic signaling. This review summarizes these findings and proposes a model combining connective tissue plasticity and peripheral sensory modulation in response to the sustained stretching of tissue that results from acupuncture needle manipulation.

  7. Peripheral Nerve Injuries and Transplantation of Olfactory Ensheathing Cells for Axonal Regeneration and Remyelination: Fact or Fiction?

    PubMed Central

    Radtke, Christine; Kocsis, Jeffery D.

    2012-01-01

    Successful nerve regeneration after nerve trauma is not only important for the restoration of motor and sensory functions, but also to reduce the potential for abnormal sensory impulse generation that can occur following neuroma formation. Satisfying functional results after severe lesions are difficult to achieve and the development of interventional methods to achieve optimal functional recovery after peripheral nerve injury is of increasing clinical interest. Olfactory ensheathing cells (OECs) have been used to improve axonal regeneration and functional outcome in a number of studies in spinal cord injury models. The rationale is that the OECs may provide trophic support and a permissive environment for axonal regeneration. The experimental transplantation of OECs to support and enhance peripheral nerve regeneration is much more limited. This chapter reviews studies using OECs as an experimental cell therapy to improve peripheral nerve regeneration. PMID:23202929

  8. High-resolution live imaging reveals axon-glia interactions during peripheral nerve injury and repair in zebrafish

    PubMed Central

    Xiao, Yan; Faucherre, Adèle; Pola-Morell, Laura; Heddleston, John M.; Liu, Tsung-Li; Chew, Teng-Leong; Sato, Fuminori; Sehara-Fujisawa, Atsuko; Kawakami, Koichi; López-Schier, Hernán

    2015-01-01

    ABSTRACT Neural damage is a devastating outcome of physical trauma. The glia are one of the main effectors of neuronal repair in the nervous system, but the dynamic interactions between peripheral neurons and Schwann cells during injury and regeneration remain incompletely characterized. Here, we combine laser microsurgery, genetic analysis, high-resolution intravital imaging and lattice light-sheet microscopy to study the interaction between Schwann cells and sensory neurons in a zebrafish model of neurotrauma. We found that chronic denervation by neuronal ablation leads to Schwann-cell death, whereas acute denervation by axonal severing does not affect the overall complexity and architecture of the glia. Neuronal-circuit regeneration begins when Schwann cells extend bridging processes to close the injury gap. Regenerating axons grow faster and directionally after the physiological clearing of distal debris by the Schwann cells. This might facilitate circuit repair by ensuring that axons are guided through unoccupied spaces within bands of Büngner towards their original peripheral target. Accordingly, in the absence of Schwann cells, regenerating axons are misrouted, impairing the re-innervation of sensory organs. Our results indicate that regenerating axons use haptotaxis as a directional cue during the reconstitution of a neural circuit. These findings have implications for therapies aimed at neurorepair, which will benefit from preserving the architecture of the peripheral glia during periods of denervation. PMID:26035865

  9. Activation of the unfolded protein response promotes axonal regeneration after peripheral nerve injury

    PubMed Central

    Oñate, Maritza; Catenaccio, Alejandra; Martínez, Gabriela; Armentano, Donna; Parsons, Geoffrey; Kerr, Bredford; Hetz, Claudio; Court, Felipe A.

    2016-01-01

    Although protein-folding stress at the endoplasmic reticulum (ER) is emerging as a driver of neuronal dysfunction in models of spinal cord injury and neurodegeneration, the contribution of this pathway to peripheral nerve damage remains poorly explored. Here we targeted the unfolded protein response (UPR), an adaptive reaction against ER stress, in mouse models of sciatic nerve injury and found that ablation of the transcription factor XBP1, but not ATF4, significantly delay locomotor recovery. XBP1 deficiency led to decreased macrophage recruitment, a reduction in myelin removal and axonal regeneration. Conversely, overexpression of XBP1s in the nervous system in transgenic mice enhanced locomotor recovery after sciatic nerve crush, associated to an improvement in key pro-regenerative events. To assess the therapeutic potential of UPR manipulation to axonal regeneration, we locally delivered XBP1s or an shRNA targeting this transcription factor to sensory neurons of the dorsal root ganglia using a gene therapy approach and found an enhancement or reduction of axonal regeneration in vivo, respectively. Our results demonstrate a functional role of specific components of the ER proteostasis network in the cellular changes associated to regeneration and functional recovery after peripheral nerve injury. PMID:26906090

  10. Rapamycin-Resistant mTOR Activity Is Required for Sensory Axon Regeneration Induced by a Conditioning Lesion

    PubMed Central

    Lu, Na; Ding, Yue; Chan, Leung Ting; Wang, Xu; Gao, Xin; Jiang, Songshan

    2016-01-01

    Abstract Neuronal mammalian target of rapamycin (mTOR) activity is a critical determinant of the intrinsic regenerative ability of mature neurons in the adult central nervous system (CNS). However, whether its action also applies to peripheral nervous system (PNS) neurons after injury remains elusive. To address this issue unambiguously, we used genetic approaches to determine the role of mTOR signaling in sensory axon regeneration in mice. We showed that deleting mTOR in dorsal root ganglion (DRG) neurons suppressed the axon regeneration induced by conditioning lesions. To establish whether the impact of mTOR on axon regeneration results from functions of mTOR complex 1 (mTORC1) or 2 (mTORC2), two distinct kinase complexes, we ablated either Raptor or Rictor in DRG neurons. We found that suppressing mTORC1 signaling dramatically decreased the conditioning lesion effect. In addition, an injury to the peripheral branch boosts mTOR activity in DRG neurons that cannot be completely inhibited by rapamycin, a widely used mTOR-specific inhibitor. Unexpectedly, examining several conditioning lesion–induced pro-regenerative pathways revealed that Raptor deletion but not rapamycin suppressed Stat3 activity in neurons. Therefore, our results demonstrate that crosstalk between mTOR and Stat3 signaling mediates the conditioning lesion effect and provide genetic evidence that rapamycin-resistant mTOR activity contributes to the intrinsic axon growth capacity in adult sensory neurons after injury. PMID:28101526

  11. Rapamycin-Resistant mTOR Activity Is Required for Sensory Axon Regeneration Induced by a Conditioning Lesion.

    PubMed

    Chen, Weitao; Lu, Na; Ding, Yue; Wang, Yuan; Chan, Leung Ting; Wang, Xu; Gao, Xin; Jiang, Songshan; Liu, Kai

    2016-01-01

    Neuronal mammalian target of rapamycin (mTOR) activity is a critical determinant of the intrinsic regenerative ability of mature neurons in the adult central nervous system (CNS). However, whether its action also applies to peripheral nervous system (PNS) neurons after injury remains elusive. To address this issue unambiguously, we used genetic approaches to determine the role of mTOR signaling in sensory axon regeneration in mice. We showed that deleting mTOR in dorsal root ganglion (DRG) neurons suppressed the axon regeneration induced by conditioning lesions. To establish whether the impact of mTOR on axon regeneration results from functions of mTOR complex 1 (mTORC1) or 2 (mTORC2), two distinct kinase complexes, we ablated either Raptor or Rictor in DRG neurons. We found that suppressing mTORC1 signaling dramatically decreased the conditioning lesion effect. In addition, an injury to the peripheral branch boosts mTOR activity in DRG neurons that cannot be completely inhibited by rapamycin, a widely used mTOR-specific inhibitor. Unexpectedly, examining several conditioning lesion-induced pro-regenerative pathways revealed that Raptor deletion but not rapamycin suppressed Stat3 activity in neurons. Therefore, our results demonstrate that crosstalk between mTOR and Stat3 signaling mediates the conditioning lesion effect and provide genetic evidence that rapamycin-resistant mTOR activity contributes to the intrinsic axon growth capacity in adult sensory neurons after injury.

  12. Sensory Biology: Novel Peripheral Organization for Better Smell.

    PubMed

    Wall, Crystal M; Zhao, Haiqing

    2015-10-05

    Sensory systems have adopted various ways to enhance detection and discrimination. A recent study shows a novel spatial organization of sensory cells in the peripheral olfactory system in mice for better odor detection.

  13. The atypical cadherin Flamingo is required for sensory axon advance beyond intermediate target cells.

    PubMed

    Steinel, Martin C; Whitington, Paul M

    2009-03-15

    The Drosophila atypical cadherin Flamingo plays key roles in a number of developmental processes. We have used the sensory nervous system of the Drosophila embryo to shed light on the mechanism by which Flamingo regulates axon growth. flamingo loss of function mutants display a highly penetrant sensory axon stall phenotype. The location of these axon stalls is stereotypic and corresponds to the position of intermediate target cells, with which sensory axons associate during normal development. This suggests that Flamingo mediates an interaction between the sensory neuron growth cones and these intermediate targets, which is required for continued axon advance. Mutant rescue experiments show that Flamingo expression is required only in sensory neurons for normal axon growth. The flamingo mutant phenotype can be partially rescued by expressing a Flamingo construct lacking most of the extracellular domain, suggesting that regulation of sensory axon advance by Flamingo does not absolutely depend upon a homophilic Flamingo-Flamingo interaction or its ability to mediate cell-cell adhesion. Loss of function mutants for a number of key genes that act together with Flamingo in the planar cell polarity pathway do not display the highly penetrant stalling phenotype seen in flamingo mutants.

  14. Peripherally-Derived BDNF Promotes Regeneration of Ascending Sensory Neurons after Spinal Cord Injury

    PubMed Central

    Zhang, Feng-He; Zhong, Jin-Hua; Zhou, Xin-Fu

    2008-01-01

    Background The blood brain barrier (BBB) and truncated trkB receptor on astrocytes prevent the penetration of brain derived neurotrophic factor (BDNF) applied into the peripheral (PNS) and central nervous system (CNS) thus restrict its application in the treatment of nervous diseases. As BDNF is anterogradely transported by axons, we propose that peripherally derived and/or applied BDNF may act on the regeneration of central axons of ascending sensory neurons. Methodology/Principal Findings The present study aimed to test the hypothesis by using conditioning lesion of the sciatic nerve as a model to increase the expression of endogenous BDNF in sensory neurons and by injecting exogenous BDNF into the peripheral nerve or tissues. Here we showed that most of regenerating sensory neurons expressed BDNF and p-CREB but not p75NTR. Conditioning-lesion induced regeneration of ascending sensory neuron and the increase in the number of p-Erk positive and GAP-43 positive neurons was blocked by the injection of the BDNF antiserum in the periphery. Enhanced neurite outgrowth of dorsal root ganglia (DRG) neurons in vitro by conditioning lesion was also inhibited by the neutralization with the BDNF antiserum. The delivery of exogenous BDNF into the sciatic nerve or the footpad significantly increased the number of regenerating DRG neurons and regenerating sensory axons in the injured spinal cord. In a contusion injury model, an injection of BDNF into the footpad promoted recovery of motor functions. Conclusions/Significance Our data suggest that endogenous BDNF in DRG and spinal cord is required for the enhanced regeneration of ascending sensory neurons after conditioning lesion of sciatic nerve and peripherally applied BDNF may have therapeutic effects on the spinal cord injury. PMID:18320028

  15. Acute motor-sensory axonal neuropathy after cervical spine surgery.

    PubMed

    Miscusi, Massimo; Currà, Antonio; Della Rocca, Carlo; Missori, Paolo; Petrozza, Vincenzo

    2012-07-01

    The authors report the case of a 55-year-old man who presented with acute motor-sensory axonal neuropathy (AMSAN), a variant of Guillain-Barré syndrome with a poor prognosis, immediately after surgery for resection of a cervical chondroma. A misdiagnosis of spinal cord shock due to an acute surgical or vascular postoperative complication was initially made in this patient. Nevertheless, there was continuous transient improvement that was followed by progressive worsening, and further investigation was necessary. The diagnosis of AMSAN, associated with acute colitis caused by Helicobacter pylori, was made based on neurophysiological examinations and colonoscopy. Interestingly, the patient also developed nephrotic syndrome, which was thought to be a further complication of the autoimmune reaction. Delayed administration of immunoglobulins (400 mg/kg/day), mesalazine (800 mg 3×/day), and meropenem (3 g/day) was used to treat the Helicobacter infection and the autoimmune reaction, leading to restoration of renal function and slight neurological improvement. The patient's general condition and neurological status improved slightly, but he remained seriously disabled (Frankel Grade C). This case demonstrates that a new onset of neurological symptoms in the early postoperative period after spine surgery could be related to causes other than iatrogenic myelopathy, and that an early diagnosis can reduce neurological sequelae, leading to a better outcome.

  16. Charcot Marie Tooth 2B Peripheral Sensory Neuropathy: How Rab7 Mutations Impact NGF Signaling?

    PubMed Central

    Liu, Harry; Wu, Chengbiao

    2017-01-01

    Charcot-Marie-Tooth 2B peripheral sensory neuropathy (CMT2B) is a debilitating autosomal dominant hereditary sensory neuropathy. Patients with this disease lose pain sensation and frequently need amputation. Axonal dysfunction and degeneration of peripheral sensory neurons is a major clinical manifestation of CMT2B. However, the cellular and molecular pathogenic mechanisms remain undefined. CMT2B is caused by missense point mutations (L129F, K157N, N161T/I, V162M) in Rab7 GTPase. Strong evidence suggests that the Rab7 mutation(s) enhances the cellular levels of activated Rab7 proteins, thus resulting in increased lysosomal activity and autophagy. As a consequence, trafficking and signaling of neurotrophic factors such as nerve growth factor (NGF) in the long axons of peripheral sensory neurons are particularly vulnerable to premature degradation. A “gain of toxicity” model has, thus, been proposed based on these observations. However, studies of fly photo-sensory neurons indicate that the Rab7 mutation(s) causes a “loss of function”, resulting in haploinsufficiency. In the review, we summarize experimental evidence for both hypotheses. We argue that better models (rodent animals and human neurons) of CMT2B are needed to precisely define the disease mechanisms. PMID:28165391

  17. Charcot Marie Tooth 2B Peripheral Sensory Neuropathy: How Rab7 Mutations Impact NGF Signaling?

    PubMed

    Liu, Harry; Wu, Chengbiao

    2017-02-04

    Charcot-Marie-Tooth 2B peripheral sensory neuropathy (CMT2B) is a debilitating autosomal dominant hereditary sensory neuropathy. Patients with this disease lose pain sensation and frequently need amputation. Axonal dysfunction and degeneration of peripheral sensory neurons is a major clinical manifestation of CMT2B. However, the cellular and molecular pathogenic mechanisms remain undefined. CMT2B is caused by missense point mutations (L129F, K157N, N161T/I, V162M) in Rab7 GTPase. Strong evidence suggests that the Rab7 mutation(s) enhances the cellular levels of activated Rab7 proteins, thus resulting in increased lysosomal activity and autophagy. As a consequence, trafficking and signaling of neurotrophic factors such as nerve growth factor (NGF) in the long axons of peripheral sensory neurons are particularly vulnerable to premature degradation. A "gain of toxicity" model has, thus, been proposed based on these observations. However, studies of fly photo-sensory neurons indicate that the Rab7 mutation(s) causes a "loss of function", resulting in haploinsufficiency. In the review, we summarize experimental evidence for both hypotheses. We argue that better models (rodent animals and human neurons) of CMT2B are needed to precisely define the disease mechanisms.

  18. New form of autosomal-recessive axonal hereditary sensory motor neuropathy.

    PubMed

    Eckhardt, S M; Hicks, E M; Herron, B; Morrison, P J; Aicardi, J

    1998-09-01

    Two siblings, a male and a female, had severe axonal neuropathy and sideroblastic anemia. Despite a distinct clinical picture with areflexia, ataxia, hypotonia, optic atrophy, and progressive sensory neural hearing loss, no definite diagnosis could be reached and the older sibling died at 6 years of age of respiratory failure. It is proposed that the two affected siblings have a new form of autosomal-recessive axonal hereditary sensory motor neuropathy.

  19. Clinical, physiological and pathological characterisation of the sensory predominant peripheral neuropathy in copper deficiency.

    PubMed

    Taylor, Sean W; Laughlin, Ruple S; Kumar, Neeraj; Goodman, Brent; Klein, Christopher J; Dyck, Peter J; Dyck, P James B

    2017-10-01

    Myelopathy is considered the most common neurological complication of copper deficiency. Concurrent peripheral neuropathy has been recognised in association with copper deficiency but has not been well characterised. To characterise the clinical, physiological and pathological features of copper-deficient peripheral neuropathy. Patients with simultaneous copper deficiency (<0.78 μg/mL) and peripheral neuropathy seen at the Mayo Clinic from 1985 to 2005 were identified. 34 patients were identified (median age 55 years, range 36-78) including 24 women and 10 men. Myelopathy was found in 21 patients. Median serum copper level was 0.11 μg/mL (range 0-0.58). The most frequent clinical and electrophysiological pattern of neuropathy was a sensory predominant length-dependent peripheral neuropathy (71%). Somatosensory evoked potentials demonstrated central slowing supporting myelopathy (96%). Quantitative sensory testing demonstrated both small and large fibre involvement (100%). Autonomic reflex screens (77%) and thermoregulatory sweat test (67%) confirmed sudomotor dysfunction. 14 cutaneous nerve biopsies revealed loss of myelinated nerve fibres (86%), increased regenerative clusters (50%), increased rates of axonal degeneration (91%) and increased numbers of empty nerve strands (73%). 71% of biopsies demonstrated epineurial perivascular inflammation. An axonal, length-dependent sensory predominant peripheral neuropathy causing sensory ataxia is characteristic of copper deficiency usually co-occurring with myelopathy. Neurophysiological testing confirms involvement of large, greater than small fibres. The pathological findings suggest axonal degeneration and repair. Inflammatory infiltrates are common but are small and of doubtful pathological significance. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  20. Schwann cell-derived exosomes enhance axonal regeneration in the peripheral nervous system.

    PubMed

    Lopez-Verrilli, María Alejandra; Picou, Frederic; Court, Felipe A

    2013-11-01

    Axonal regeneration in the peripheral nervous system is greatly supported by Schwann cells (SCs). After nerve injury, SCs dedifferentiate to a progenitor-like state and efficiently guide axons to their original target tissues. Contact and soluble factors participate in the crosstalk between SCs and axons during axonal regeneration. Here we show that dedifferentiated SCs secrete nano-vesicles known as exosomes which are specifically internalized by axons. Surprisingly, SC-derived exosomes markedly increase axonal regeneration in vitro and enhance regeneration after sciatic nerve injury in vivo. Exosomes shift the growth cone morphology to a pro-regenerating phenotype and decrease the activity of the GTPase RhoA, involved in growth cone collapse and axon retraction. Altogether, our work identifies a novel mechanism by which SCs communicate with neighboring axons during regenerative processes. We propose that SC exosomes represent an important mechanism by which these cells locally support axonal maintenance and regeneration after nerve damage.

  1. Dorsal column sensory axons degenerate due to impaired microvascular perfusion after spinal cord injury in rats

    PubMed Central

    Muradov, Johongir M.; Ewan, Eric E.; Hagg, Theo

    2013-01-01

    The mechanisms contributing to axon loss after spinal cord injury (SCI) are largely unknown but may involve microvascular loss as we have previously suggested. Here, we used a mild contusive injury (120 kdyn IH impactor) at T9 in rats focusing on ascending primary sensory dorsal column axons, anterogradely traced from the sciatic nerves. The injury caused a rapid and progressive loss of dorsal column microvasculature and oligodendrocytes at the injury site and penumbra and a ~70% loss of the sensory axons, by 24 hours. To model the microvascular loss, focal ischemia of the T9 dorsal columns was achieved via phototoxic activation of intravenously injected rose bengal. This caused an ~53% loss of sensory axons and an ~80% loss of dorsal column oligodendrocytes by 24 hours. Axon loss correlated with the extent and axial length of microvessel and oligodendrocyte loss along the dorsal column. To determine if oligodendrocyte loss contributes to axon loss, the glial toxin ethidium bromide (EB; 0.3 µg/µl) was microinjected into the T9 dorsal columns, and resulted in an ~88% loss of dorsal column oligodendrocytes and an ~56% loss of sensory axons after 72 hours. EB also caused an ~72% loss of microvessels. Lower concentrations of EB resulted in less axon, oligodendrocyte and microvessel loss, which were highly correlated (R2 = 0.81). These data suggest that focal spinal cord ischemia causes both oligodendrocyte and axon degeneration, which are perhaps linked. Importantly, they highlight the need of limiting the penumbral spread of ischemia and oligodendrocyte loss after SCI in order to protect axons. PMID:23978615

  2. Dorsal column sensory axons degenerate due to impaired microvascular perfusion after spinal cord injury in rats.

    PubMed

    Muradov, Johongir M; Ewan, Eric E; Hagg, Theo

    2013-11-01

    The mechanisms contributing to axon loss after spinal cord injury (SCI) are largely unknown but may involve microvascular loss as we have previously suggested. Here, we used a mild contusive injury (120 kdyn IH impactor) at T9 in rats focusing on ascending primary sensory dorsal column axons, anterogradely traced from the sciatic nerves. The injury caused a rapid and progressive loss of dorsal column microvasculature and oligodendrocytes at the injury site and penumbra and an ~70% loss of the sensory axons by 24 h. To model the microvascular loss, focal ischemia of the T9 dorsal columns was achieved via phototoxic activation of intravenously injected rose bengal. This caused an ~53% loss of sensory axons and an ~80% loss of dorsal column oligodendrocytes by 24 h. Axon loss correlated with the extent and axial length of microvessel and oligodendrocyte loss along the dorsal column. To determine if oligodendrocyte loss contributes to axon loss, the glial toxin ethidium bromide (EB; 0.3 μg/μl) was microinjected into the T9 dorsal columns, and resulted in an ~88% loss of dorsal column oligodendrocytes and an ~56% loss of sensory axons after 72 h. EB also caused an ~75% loss of microvessels. Lower concentrations of EB resulted in less axon, oligodendrocyte and microvessel loss, which were highly correlated (R(2) = 0.81). These data suggest that focal spinal cord ischemia causes both oligodendrocyte and axon degeneration, which are perhaps linked. Importantly, they highlight the need of limiting the penumbral spread of ischemia and oligodendrocyte loss after SCI in order to protect axons. © 2013.

  3. Morphological and molecular features of the mammalian olfactory sensory neuron axons: What makes these axons so special?

    PubMed

    Nedelec, Stéphane; Dubacq, Caroline; Trembleau, Alain

    2005-03-01

    The main organization and gross morphology of the mammalian olfactory primary pathway, from the olfactory epithelium to the olfactory bulb, has been initially characterized using classical anatomical and ultrastructural approaches. During the last fifteen years, essentially thanks to the cloning of the odorant receptor genes, and to the characterization of a number of molecules expressed by the olfactory sensory neuron axons and their environment, significant new insights have been gained into the understanding of the development and adult functioning of this system. In the course of these genetic, biochemical and neuroanatomical studies, however, several molecular and structural features were uncovered that appear somehow to be unique to these axons. For example, these axons express odorant receptors in their terminal segment, and transport several mRNA species and at least two transcription factors. In the present paper, we review these unusual structural and molecular features and speculate about their possible functions in the development and maintenance of the olfactory system.

  4. Odorant receptors regulate the final glomerular coalescence of olfactory sensory neuron axons.

    PubMed

    Rodriguez-Gil, Diego J; Bartel, Dianna L; Jaspers, Austin W; Mobley, Arie S; Imamura, Fumiaki; Greer, Charles A

    2015-05-05

    Odorant receptors (OR) are strongly implicated in coalescence of olfactory sensory neuron (OSN) axons and the formation of olfactory bulb (OB) glomeruli. However, when ORs are first expressed relative to basal cell division and OSN axon extension is unknown. We developed an in vivo fate-mapping strategy that enabled us to follow OSN maturation and axon extension beginning at basal cell division. In parallel, we mapped the molecular development of OSNs beginning at basal cell division, including the onset of OR expression. Our data show that ORs are first expressed around 4 d following basal cell division, 24 h after OSN axons have reached the OB. Over the next 6+ days the OSN axons navigate the OB nerve layer and ultimately coalesce in glomeruli. These data provide a previously unidentified perspective on the role of ORs in homophilic OSN axon adhesion and lead us to propose a new model dividing axon extension into two phases. Phase I is OR-independent and accounts for up to 50% of the time during which axons approach the OB and begin navigating the olfactory nerve layer. Phase II is OR-dependent and concludes as OSN axons coalesce in glomeruli.

  5. Odorant receptors regulate the final glomerular coalescence of olfactory sensory neuron axons

    PubMed Central

    Rodriguez-Gil, Diego J.; Bartel, Dianna L.; Jaspers, Austin W.; Mobley, Arie S.; Imamura, Fumiaki; Greer, Charles A.

    2015-01-01

    Odorant receptors (OR) are strongly implicated in coalescence of olfactory sensory neuron (OSN) axons and the formation of olfactory bulb (OB) glomeruli. However, when ORs are first expressed relative to basal cell division and OSN axon extension is unknown. We developed an in vivo fate-mapping strategy that enabled us to follow OSN maturation and axon extension beginning at basal cell division. In parallel, we mapped the molecular development of OSNs beginning at basal cell division, including the onset of OR expression. Our data show that ORs are first expressed around 4 d following basal cell division, 24 h after OSN axons have reached the OB. Over the next 6+ days the OSN axons navigate the OB nerve layer and ultimately coalesce in glomeruli. These data provide a previously unidentified perspective on the role of ORs in homophilic OSN axon adhesion and lead us to propose a new model dividing axon extension into two phases. Phase I is OR-independent and accounts for up to 50% of the time during which axons approach the OB and begin navigating the olfactory nerve layer. Phase II is OR-dependent and concludes as OSN axons coalesce in glomeruli. PMID:25902488

  6. Expression of an Activated Integrin Promotes Long-Distance Sensory Axon Regeneration in the Spinal Cord.

    PubMed

    Cheah, Menghon; Andrews, Melissa R; Chew, Daniel J; Moloney, Elizabeth B; Verhaagen, Joost; Fässler, Reinhard; Fawcett, James W

    2016-07-06

    After CNS injury, axon regeneration is blocked by an inhibitory environment consisting of the highly upregulated tenascin-C and chondroitin sulfate proteoglycans (CSPGs). Tenascin-C promotes growth of axons if they express a tenascin-binding integrin, particularly α9β1. Additionally, integrins can be inactivated by CSPGs, and this inhibition can be overcome by the presence of a β1-binding integrin activator, kindlin-1. We examined the synergistic effect of α9 integrin and kindlin-1 on sensory axon regeneration in adult rat spinal cord after dorsal root crush and adeno-associated virus transgene expression in dorsal root ganglia. After 12 weeks, axons from C6-C7 dorsal root ganglia regenerated through the tenascin-C-rich dorsal root entry zone into the dorsal column up to C1 level and above (>25 mm axon length) through a normal pathway. Animals also showed anatomical and electrophysiological evidence of reconnection to the dorsal horn and behavioral recovery in mechanical pressure, thermal pain, and ladder-walking tasks. Expression of α9 integrin or kindlin-1 alone promoted much less regeneration and recovery. The study demonstrates that long-distance sensory axon regeneration over a normal pathway and with sensory and sensory-motor recovery can be achieved. This was achieved by expressing an integrin that recognizes tenascin-C, one of the components of glial scar tissue, and an integrin activator. This enabled extensive long-distance (>25 mm) regeneration of both myelinated and unmyelinated sensory axons with topographically correct connections in the spinal cord. The extent of growth and recovery we have seen would probably be clinically significant. Restoration of sensation to hands, perineum, and genitalia would be a significant improvement for a spinal cord-injured patient. Copyright © 2016 CHEAH et al.

  7. Axons provide the secretory machinery for trafficking of voltage-gated sodium channels in peripheral nerve

    PubMed Central

    González, Carolina; Cánovas, José; Fresno, Javiera; Couve, Eduardo; Court, Felipe A.; Couve, Andrés

    2016-01-01

    The regulation of the axonal proteome is key to generate and maintain neural function. Fast and slow axoplasmic waves have been known for decades, but alternative mechanisms to control the abundance of axonal proteins based on local synthesis have also been identified. The presence of the endoplasmic reticulum has been documented in peripheral axons, but it is still unknown whether this localized organelle participates in the delivery of axonal membrane proteins. Voltage-gated sodium channels are responsible for action potentials and are mostly concentrated in the axon initial segment and nodes of Ranvier. Despite their fundamental role, little is known about the intracellular trafficking mechanisms that govern their availability in mature axons. Here we describe the secretory machinery in axons and its contribution to plasma membrane delivery of sodium channels. The distribution of axonal secretory components was evaluated in axons of the sciatic nerve and in spinal nerve axons after in vivo electroporation. Intracellular protein trafficking was pharmacologically blocked in vivo and in vitro. Axonal voltage-gated sodium channel mRNA and local trafficking were examined by RT-PCR and a retention-release methodology. We demonstrate that mature axons contain components of the endoplasmic reticulum and other biosynthetic organelles. Axonal organelles and sodium channel localization are sensitive to local blockade of the endoplasmic reticulum to Golgi transport. More importantly, secretory organelles are capable of delivering sodium channels to the plasma membrane in isolated axons, demonstrating an intrinsic capacity of the axonal biosynthetic route in regulating the axonal proteome in mammalian axons. PMID:26839409

  8. Severity of Demyelinating and Axonal Neuropathy Mouse Models Is Modified by Genes Affecting Structure and Function of Peripheral Nodes.

    PubMed

    Morelli, Kathryn H; Seburn, Kevin L; Schroeder, David G; Spaulding, Emily L; Dionne, Loiuse A; Cox, Gregory A; Burgess, Robert W

    2017-03-28

    Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous group of inherited polyneuropathies. Mutations in 80 genetic loci can cause forms of CMT, resulting in demyelination and axonal dysfunction. The clinical presentation, including sensory deficits, distal muscle weakness, and atrophy, can vary greatly in severity and progression. Here, we used mouse models of CMT to demonstrate genetic interactions that result in a more severe neuropathy phenotype. The cell adhesion molecule Nrcam and the Na(+) channel Scn8a (NaV1.6) are important components of nodes. Homozygous Nrcam and heterozygous Scn8a mutations synergized with both an Sh3tc2 mutation, modeling recessive demyelinating Charcot-Marie-Tooth type 4C, and mutations in Gars, modeling dominant axonal Charcot-Marie-Tooth type 2D. We conclude that genetic variants perturbing the structure and function of nodes interact with mutations affecting the cable properties of axons by thinning myelin or reducing axon diameter. Therefore, genes integral to peripheral nodes are candidate modifiers of peripheral neuropathy.

  9. Calcium signalling in sensory neurones and peripheral glia in the context of diabetic neuropathies.

    PubMed

    Verkhratsky, Alexei; Fernyhough, Paul

    2014-11-01

    Peripheral sensory nervous system is comprised of neurones with their axons and neuroglia that includes satellite glial cells in sensory ganglia, myelinating, non-myelinating and perisynaptic Schwann cells. Pathogenesis of peripheral diabetic polyneuropathies is associated with aberrant function of both neurones and glia. Deregulated Ca(2+) homoeostasis and aberrant Ca(2+) signalling in neuronal and glial elements contributes to many forms of neuropathology and is fundamental to neurodegenerative diseases. In diabetes both neurones and glia experience metabolic stress and mitochondrial dysfunction which lead to deregulation of Ca(2+) homeostasis and Ca(2+) signalling, which in their turn lead to pathological cellular reactions contributing to development of diabetic neuropathies. Molecular cascades responsible for Ca(2+) homeostasis and signalling, therefore, can be regarded as potential therapeutic targets. Copyright © 2014 Elsevier Ltd. All rights reserved.

  10. Biology of peripheral inherited neuropathies: Schwann cell axonal interactions.

    PubMed

    Shy, Michael E

    2009-01-01

    Development and maintenance of PNS myelin depends on continual signaling from axons ensheathed by myelin. Recent advances have demonstrated the roles of neuregulin 1 type III, Erb2/3 and intracellular signal transduction pathways in inducing Schwann cell myelination. Alternatively, maintenance of myelinated axons depends on healthy myelinating Schwann cells. Axonal degeneration is a feature of virtually all inherited demyelinating neuropathies and in many cases is more responsible for clinical impairment than the primary demyelination. Signaling mechanisms through which demyelinating Schwann cells damage axons are not well understood. In this review several examples of potential mechanisms by which demyelinating neuropathies damage axons will be presented. Understanding the molecular basis of Schwann cell-axonal interactions will not only increase the understanding of PNS biology but also identify therapeutic targets for inherited neuropathies.

  11. Expression of an Activated Integrin Promotes Long-Distance Sensory Axon Regeneration in the Spinal Cord

    PubMed Central

    Cheah, Menghon; Chew, Daniel J.; Moloney, Elizabeth B.; Verhaagen, Joost; Fässler, Reinhard

    2016-01-01

    After CNS injury, axon regeneration is blocked by an inhibitory environment consisting of the highly upregulated tenascin-C and chondroitin sulfate proteoglycans (CSPGs). Tenascin-C promotes growth of axons if they express a tenascin-binding integrin, particularly α9β1. Additionally, integrins can be inactivated by CSPGs, and this inhibition can be overcome by the presence of a β1-binding integrin activator, kindlin-1. We examined the synergistic effect of α9 integrin and kindlin-1 on sensory axon regeneration in adult rat spinal cord after dorsal root crush and adeno-associated virus transgene expression in dorsal root ganglia. After 12 weeks, axons from C6–C7 dorsal root ganglia regenerated through the tenascin-C-rich dorsal root entry zone into the dorsal column up to C1 level and above (>25 mm axon length) through a normal pathway. Animals also showed anatomical and electrophysiological evidence of reconnection to the dorsal horn and behavioral recovery in mechanical pressure, thermal pain, and ladder-walking tasks. Expression of α9 integrin or kindlin-1 alone promoted much less regeneration and recovery. SIGNIFICANCE STATEMENT The study demonstrates that long-distance sensory axon regeneration over a normal pathway and with sensory and sensory–motor recovery can be achieved. This was achieved by expressing an integrin that recognizes tenascin-C, one of the components of glial scar tissue, and an integrin activator. This enabled extensive long-distance (>25 mm) regeneration of both myelinated and unmyelinated sensory axons with topographically correct connections in the spinal cord. The extent of growth and recovery we have seen would probably be clinically significant. Restoration of sensation to hands, perineum, and genitalia would be a significant improvement for a spinal cord-injured patient. PMID:27383601

  12. Axonal Elongation into Peripheral Nervous System ``Bridges'' after Central Nervous System Injury in Adult Rats

    NASA Astrophysics Data System (ADS)

    David, Samuel; Aguayo, Albert J.

    1981-11-01

    The origin, termination, and length of axonal growth after focal central nervous system injury was examined in adult rats by means of a new experimental model. When peripheral nerve segments were used as ``bridges'' between the medulla and spinal cord, axons from neurons at both these levels grew approximately 30 millimeters. The regenerative potential of these central neurons seems to be expressed when the central nervous system glial environment is changed to that of the peripheral nervous system.

  13. Sensory loss, pains, motor deficit and axonal regeneration in length-dependent diabetic polyneuropathy.

    PubMed

    Said, G; Baudoin, D; Toyooka, K

    2008-11-01

    In order to learn more on the occurrence of pains and motor deficit in severe diabetic polyneuropathy we reviewed the data of a series of 30 diabetic patients with an uncommonly severe length-dependent diabetic polyneuropathy (LDDP). Extensive sensory loss predominated with pains and temperature sensations and affected all four limb extremities, anterior trunk in all, plus the top of the scalp in 9 patients and the cauda equina territory in 2. Twenty patients had neuropathic pains. Symptomatic autonomic dysfunction was present in 28/30 patients, mild distal motor deficit in 12 patients, severe in only one. Vibratory sensation was impaired in the lower limbs in 18 patients; position sense in 8. In the 10 nerve biopsy specimens, the density of myelinated axons was reduced to 23 % and that of unmyelinated axons to 8.5 % of control values. Regenerating axons accounted for 32.4 +/- 19.8 % of the myelinated fibres. On teased fibre preparations 13.9 % of fibres were undergoing axonal degeneration, while 29.4 % of fibres showed focal abnormalities of the myelin sheath.We conclude that distal motor deficit occurs only after major loss of sensory fibres in LDDP; the unmyelinated axons are predominantly affected; absence of clinical improvement contrasts with the high proportion of regenerating axons; detection of alteration of pain and temperature sensation in the feet seems the best method for neuropathy screening in diabetic patients.

  14. Dorsal Root Ganglia Sensory Neuronal Cultures: a tool for drug discovery for peripheral neuropathies

    PubMed Central

    Melli, Giorgia; Höke, Ahmet

    2010-01-01

    Background Peripheral neuropathies affect many people worldwide and are caused by or associated with a wide range of conditions, both genetic and acquired. Current therapies are directed at symptomatic control because no effective regenerative treatment exists. Primary challenge is that mechanisms that lead to distal axonal degeneration, a common feature of all peripheral neuropathies, are largely unknown. Objective/Methods To address the role and specific characteristics of dorsal root ganglia (DRG) derived sensory neuron culture system as a useful model in evaluating the pathogenic mechanisms of peripheral neuropathies and examination and validation of potential therapeutic compounds. A thorough review of the recent literature was completed and select examples of the use of DRG neurons in different peripheral neuropathy models were chosen to highlight the utility of these cultures. Conclusion Many useful models of different peripheral neuropathies have been developed using DRG neuronal culture and potential therapeutic targets have been examined, but so far none of the potential therapeutic compounds have succeeded in clinical trials. In recent years, focus has changed to evaluation of axon degeneration as the primary outcome measure advocating a drug development strategy starting with phenotypic drug screening, followed by validation in primary complex co-cultures and animal models. PMID:20657751

  15. Differential expression of axon-sorting molecules in mouse olfactory sensory neurons.

    PubMed

    Ihara, Naoki; Nakashima, Ai; Hoshina, Naosuke; Ikegaya, Yuji; Takeuchi, Haruki

    2016-08-01

    In the mouse olfactory system, the axons of olfactory sensory neurons that express the same type of odorant receptor (OR) converge to a specific set of glomeruli in the olfactory bulb (OB). It is widely accepted that expressed OR molecules instruct glomerular segregation by regulating the expression of axon-sorting molecules. Although the relationship between the expression of axon-sorting molecules and OR types has been analyzed in detail, those between the expressions of axon-sorting molecules remain to be elucidated. Here we collected the expression profiles of four axon-sorting molecules from a large number of glomeruli in the OB. These molecules demonstrated position-independent mosaic expressions, but their patterns were not identical in the OB. Comparing their expressions identified positive and negative correlations between several pairs of genes even though they showed various expressions. Furthermore, the principal component analysis revealed that the factor loadings in the principal component 1, which explain the largest amount of variation, were most likely to reflect the degree of the cyclic nucleotide-gated (CNG) channel dependence on the expression of axon-sorting molecules. Thus, neural activity generated through the CNG channel is a major component in the generation of a wide variety of expressions of axon-sorting molecules in glomerular segregation. © 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  16. Competition with Primary Sensory Afferents Drives Remodeling of Corticospinal Axons in Mature Spinal Motor Circuits.

    PubMed

    Jiang, Yu-Qiu; Zaaimi, Boubker; Martin, John H

    2016-01-06

    after injury. Axons of the major descending motor pathway for motor skills, the corticospinal tract (CST), sprout after brain or spinal cord injury. This contributes to spontaneous spinal motor circuit repair and partial motor recovery. Knowing the determinants that enhance this plasticity is critical for functional rehabilitation. Here we examine the remodeling of CST axons directed by sensory fibers. We found that the CST projection is regulated dynamically in maturity by the competitive, activity-dependent actions of sensory fibers. Knowledge of the properties of this competition enables prediction of the remodeling of CST connections and spinal circuits after injury and informs ways to engineer target-specific control of CST connections to promote recovery. Copyright © 2016 the authors 0270-6474/16/360193-11$15.00/0.

  17. Competition with Primary Sensory Afferents Drives Remodeling of Corticospinal Axons in Mature Spinal Motor Circuits

    PubMed Central

    Jiang, Yu-Qiu; Zaaimi, Boubker

    2016-01-01

    , but it is promoted after injury. Axons of the major descending motor pathway for motor skills, the corticospinal tract (CST), sprout after brain or spinal cord injury. This contributes to spontaneous spinal motor circuit repair and partial motor recovery. Knowing the determinants that enhance this plasticity is critical for functional rehabilitation. Here we examine the remodeling of CST axons directed by sensory fibers. We found that the CST projection is regulated dynamically in maturity by the competitive, activity-dependent actions of sensory fibers. Knowledge of the properties of this competition enables prediction of the remodeling of CST connections and spinal circuits after injury and informs ways to engineer target-specific control of CST connections to promote recovery. PMID:26740661

  18. Statin use and peripheral sensory perception: a pilot study.

    PubMed

    West, Brenton; Williams, Cylie M; Jilbert, Elise; James, Alicia M; Haines, Terry P

    2014-06-01

    Peripheral sensory neuropathy is a neurological deficit resulting in decreased detection of sensation through the peripheral nervous system. Peripheral sensory neuropathy is commonly diagnosed with the use of a monofilament and either a tuning fork or neurothesiometer. Statins are a widely used medication and there has been some debate of association with their use and peripheral sensory neuropathy. This pilot study aimed to test the sensory perception of participants with long-term statin use and compare these results to their peers who were not taking statins. Thirty participants were recruited and equally divided into a statin and non-statin group. Healthy participants were screened by their medical and medication history, Australian Type 2 Diabetes Risk assessment, and random blood glucose level. An assessor who was blinded to the participant group conducted sensory assessments using a 10 g monofilament and neurothesiometer. There was no difference in monofilament testing results between the groups. The statin group was less sensate at the styloid process (p = 0.031) and medial malleolus (p = 0.003) than the control group. Results at the hallux were not statistically significant (p = 0.183). This result is suggestive of a potential association between long-term statin use and a decrease in peripheral sensory perception. This may be because of peripheral sensory neuropathy. Limitations such as consideration of participant height, participant numbers, and inability to analyze results against statin groups are reported. As statins are a life-saving medication, careful consideration should be applied to these results and further research be conducted to determine if these results are applicable to larger populations.

  19. Normal axonal ion channel function in large peripheral nerve fibers following chronic ciguatera sensitization.

    PubMed

    Vucic, Steve; Kiernan, Matthew C

    2008-03-01

    Although the acute clinical effects of ciguatera poisoning, due to ingestion of ciguatoxin, are mediated by activation of transient Na+ channels, the mechanisms underlying ciguatera sensitization remain undefined. Axonal excitability studies were performed by stimulating the median motor and sensory nerves in two patients with ciguatera sensitization. Excitability parameters were all within normal limits, thereby arguing against dysfunction of axonal membrane ion channels in large-diameter fibers in ciguatera sensitization.

  20. Dynamics of axonal mRNA transport and implications for peripheral nerve regeneration

    PubMed Central

    Yoo, Soonmoon; van Niekerk, Erna A.; Merianda, Tanuja T.; Twiss, Jeffery L.

    2009-01-01

    Locally generating new proteins in subcellular regions provides means to spatially and temporally modify protein content in polarized cells. Recent years have seen resurgence of the concept that axonal processes of neurons can locally synthesize proteins. Experiments from a number of groups have now shown that axonal protein synthesis helps to initiate growth, provides a means to respond to guidance cues, and generates retrograde signaling complexes. Additionally, there is increasing evidence that locally synthesized proteins provide functions beyond injury responses and growth in the mature peripheral nervous system. A key regulatory event in this translational regulation is moving the mRNA templates into the axonal compartment. Transport of mRNAs into axons is a highly regulated and specific process that requires interaction of RNA binding proteins with specific cis-elements or structures within the mRNAs. mRNAs are transported in ribonucleoprotein particles that interact with microtubule motor proteins for long-range axonal transport and likely use microfilaments for short-range movement in the axons. The mature axon is able to recruit mRNAs into translation with injury and possibly other stimuli suggesting that mRNAs can be stored in a dormant state in the distal axon until needed. Axotomy triggers a shift in the populations of mRNAs localized to axons indicating a dynamic regulation of the specificity of the axonal transport machinery. In this review, we discuss how axonal mRNA transport and localization are regulated to achieve specific changes in axonal RNA content in response to axonal stimuli. PMID:19699200

  1. Acute motor-sensory axonal neuropathy with hyperreflexia in Guillain-Barré syndrome.

    PubMed

    Tosun, Ayşe; Dursun, Şiar; Akyildiz, Utku Ogan; Oktay, Seçil; Tataroğlu, Cengiz

    2015-04-01

    Guillain-Barré syndrome is an acute inflammatory autoimmune polyradiculoneuritis. Progressive motor weakness and areflexia are essential for its diagnosis. Hyperreflexia has rarely been reported in the early healing period of Guillain-Barré syndrome following Campylobacter jejuni infection in patients with acute motor axonal neuropathy with antiganglioside antibody positivity. In this study, we report a 12-year-old girl presenting with complaints of inability to walk, numbness in hands and feet, and hyperactive deep tendon reflexes since the onset of the clinical picture, diagnosed with acute motor-sensory axonal neuropathy type of Guillain-Barré syndrome. © The Author(s) 2014.

  2. Sensory-motor axonal polyneuropathy involving cranial nerves: An uncommon manifestation of disulfiram toxicity.

    PubMed

    Santos, Telma; Martins Campos, António; Morais, Hugo

    2017-01-01

    Disulfiram (tetraethylthiuram disulfide) has been used for the treatment of alcohol dependence. An axonal sensory-motor polyneuropathy with involvement of cranial pairs due to disulfiram is exceedingly rare. The authors report a unique case of an extremely severe axonal polyneuropathy involving cranial nerves that developed within weeks after a regular dosage of 500mg/day disulfiram. To the authors best knowledge, such a severe and rapidly-progressive course has never been described with disulfiram dosages of only 500mg/day.

  3. Electrical Stimulation to Enhance Axon Regeneration After Peripheral Nerve Injuries in Animal Models and Humans.

    PubMed

    Gordon, Tessa

    2016-04-01

    Injured peripheral nerves regenerate their lost axons but functional recovery in humans is frequently disappointing. This is so particularly when injuries require regeneration over long distances and/or over long time periods. Fat replacement of chronically denervated muscles, a commonly accepted explanation, does not account for poor functional recovery. Rather, the basis for the poor nerve regeneration is the transient expression of growth-associated genes that accounts for declining regenerative capacity of neurons and the regenerative support of Schwann cells over time. Brief low-frequency electrical stimulation accelerates motor and sensory axon outgrowth across injury sites that, even after delayed surgical repair of injured nerves in animal models and patients, enhances nerve regeneration and target reinnervation. The stimulation elevates neuronal cyclic adenosine monophosphate and, in turn, the expression of neurotrophic factors and other growth-associated genes, including cytoskeletal proteins. Electrical stimulation of denervated muscles immediately after nerve transection and surgical repair also accelerates muscle reinnervation but, at this time, how the daily requirement of long-duration electrical pulses can be delivered to muscles remains a practical issue prior to translation to patients. Finally, the technique of inserting autologous nerve grafts that bridge between a donor nerve and an adjacent recipient denervated nerve stump significantly improves nerve regeneration after delayed nerve repair, the donor nerves sustaining the capacity of the denervated Schwann cells to support nerve regeneration. These reviewed methods to promote nerve regeneration and, in turn, to enhance functional recovery after nerve injury and surgical repair are sufficiently promising for early translation to the clinic.

  4. Retrograde axonal transport of LIF is increased by peripheral nerve injury: correlation with increased LIF expression in distal nerve.

    PubMed

    Curtis, R; Scherer, S S; Somogyi, R; Adryan, K M; Ip, N Y; Zhu, Y; Lindsay, R M; DiStefano, P S

    1994-01-01

    Leukemia inhibitory factor (LIF) is a cytokine that affects the survival and differentiation of certain neuronal populations in vitro. To identify LIF-responsive neurons in the adult rat, we have demonstrated retrograde axonal transport of 125I-LIF to sensory and motor neurons. The accumulation of 125I-LIF by both cell types was significantly increased by prior sciatic nerve crush. Retrograde transport of 125I-LIF was inhibited by excess unlabeled LIF but not by related cytokines, indicating a specific receptor-mediated mechanism. Northern blot analysis revealed LIF expression in peripheral nerve that was increased in distal segments after axotomy. The correlation between LIF expression and increased retrograde transport following injury suggests that LIF plays a role in peripheral nerve regeneration.

  5. STAT3 phosphorylation in injured axons before sensory and motor neuron nuclei: potential role for STAT3 as a retrograde signaling transcription factor.

    PubMed

    Lee, Nancy; Neitzel, Karen L; Devlin, Brenda K; MacLennan, A John

    2004-07-05

    STAT3 is a latent transcription factor that is activated by plasma membrane growth factor receptor complexes. Conditional gene disruption data indicate that it contributes to the survival of cranial motor neurons after peripheral nerve lesion. In agreement, levels of activated STAT3 (Tyr705-phosphorylated STAT3) have been shown to increase in the nuclei of adult cranial motor neurons during their regeneration after the same injury. The data presented here demonstrate that STAT3 is similarly but not identically affected in sciatic motor neurons after sciatic nerve injury. In addition, we find that sensory neuron nuclei also display an analogous increase in activated STAT3, thereby supporting a role for STAT3 in the survival and regeneration of these cells. Most interesting, the present data indicate that peripheral nerve lesion leads to a very rapid activation of STAT3 in axons at the lesion site. This response increases during the first 24 hours after injury and extends back to the motor and sensory neurons such that phospho-STAT3-immunoreactive axons are first detected in the dorsal root ganglia and ventral spinal cord at the same postlesion time intervals at which the activated STAT3 is first detected in the neuronal nuclei. Together these data raise the possibility that axonal STAT3, activated at the injury site, acts as a retrograde signaling transcription factor, which promotes the survival and regeneration of both sensory and motor neurons.

  6. Defective axonal transport: A common pathological mechanism in inherited and acquired peripheral neuropathies.

    PubMed

    Prior, Robert; Van Helleputte, Lawrence; Benoy, Veronick; Van Den Bosch, Ludo

    2017-09-01

    Peripheral neuropathies are characterized by a progressive and length-dependent loss of peripheral nerve function. This can be caused either by genetic defects, classified as 'inherited peripheral neuropathies', or they can be acquired throughout life. In that case, the disease is caused by various insults such as toxins and mechanical injuries, or it can arise secondary to medical conditions such as metabolic disorders, nutritional deficiencies, inflammation and infections. Peripheral neuropathies are not only very heterogeneous in etiology, but also in their pathology and clinical presentation. A commonality amongst all peripheral neuropathies is that no pharmacological disease-modifying therapies currently exist that can reverse or cure these diseases. Moreover, the length-dependent nature of the disease, affecting the longest nerves at the most distal sites, suggests an important role for disturbances in axonal transport, directly or indirectly linked to alterations in the cytoskeleton. In this review, we will give a systematic overview of the main arguments for the involvement of axonal transport defects in both inherited and acquired peripheral neuropathies. In addition, we will discuss the possible therapeutic strategies that can potentially counteract these disturbances, as this particular pathway might be a promising strategy to find a cure. Since counteracting axonal transport defects could limit the axonal degeneration and could be a driving force for neuronal regeneration, the benefits might be twofold. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  7. Ixabepilone-induced mitochondria and sensory axon loss in breast cancer patients.

    PubMed

    Ebenezer, Gigi J; Carlson, Karen; Donovan, Diana; Cobham, Marta; Chuang, Ellen; Moore, Anne; Cigler, Tessa; Ward, Maureen; Lane, Maureen E; Ramnarain, Anita; Vahdat, Linda T; Polydefkis, Michael

    2014-09-01

    We sought to define the clinical and ultrastructure effects of ixabepilone (Ix), a microtubule-stabilizing chemotherapy agent on cutaneous sensory nerves and to investigate a potential mitochondrial toxicity mechanism. Ten breast cancer patients receiving Ix underwent total neuropathy score clinical (TNSc) assessment, distal leg skin biopsies at cycle (Cy) 3 (80-90 mg/m(2)), Cy5 (160-190 mg/m(2)), and Cy7 (>200 mg/m(2)) and were compared to 5 controls. Skin blocks were processed for EM and ultrastructural morphometry of Remak axons done. At baseline, Ix-treated subjects had higher TNSc values (4.5 ± 0.8 vs. 0.0 ± 0.0), greater percentage of empty (denervated) Schwann cells (29% vs. 12%), altered axonal diameter (422.9 ± 17 vs. 354.9 ± 14.8 nm, P = 0.01), and axon profiles without mitochondria tended to increase compared to control subjects (71% vs. 70%). With increasing cumulative Ix exposure, an increase in TNSc values (Cy3: 5.4 ± 1.2, Cy7: 10 ± 4, P < 0.001), empty Schwann cells (39% by Cy7), and dilated axons (in nm, Cy3: 506.3 ± 22.1, Cy5: 534.8 ± 33, Cy7: 527.8 ± 24.4; P < 0.001) was observed. In addition, axon profiles without mitochondria (Cy3:74%, Cy7:78%) and mitochondria with abnormal morphology (grade 3 or 4) increased from 24% to 79%. Schwann cells with atypical mitochondria and perineuronal macrophage infiltration in dermis were noted. This study provides functional and structural evidence that Ix exposure induces a dose-dependent toxicity on small sensory fibers with an increase in TNSc scores and progressive axonal loss. Mitochondria appear to bear the cumulative toxic effect and chemotherapy-induced toxicity can be monitored through serial skin biopsy-based analysis.

  8. Schwann cell phenotype is regulated by axon modality and central-peripheral location, and persists in vitro.

    PubMed

    Brushart, T M; Aspalter, M; Griffin, J W; Redett, R; Hameed, H; Zhou, C; Wright, M; Vyas, A; Höke, A

    2013-09-01

    Myelinating Schwann cells express distinct sensory and motor phenotypes as defined by their differing patterns of growth factor production (Hoke et al., 2006). The heterogeneous growth factor requirements of sensory and motor neurons, however, suggest that Schwann cell phenotype might vary across a broad spectrum. To explore this possibility, we selectively denervated six discrete Schwann cell populations: dorsal root, cutaneous nerve, cutaneous unmyelinated axons, muscle nerve afferents, muscle nerve efferents, and ventral root. Real-time RT-PCR for 11 growth factors was performed on the 6 target Schwann cell populations 5, 15, and 30 days after their denervation, and on normal cutaneous nerve, muscle nerve, ventral root, and dorsal root to establish baseline expression levels. Within the denervated axon populations, IGF-1 and VEGF were expressed most prominently in cutaneous nerve, HGF, NGF, and BDNF in cutaneous nerve and dorsal root, GDNF in dorsal root and ventral root, PTN in the ventral root and muscle nerve efferents, and IGF-2 in both afferents and efferents within muscle nerve; expression of CNTF, FGF-2 and NT-3 was not modality or location specific. ELISA for NGF, BDNF, and GDNF confirmed that gene expression correlated with protein concentration. These findings demonstrate that growth factor expression by denervated Schwann cells is not only subject to further regulation within the previously-defined sensory and motor groups, but also varies along a central-peripheral axis. The traditional view of myelinating Schwann cells as a homogenous population is modified by the realization that complex regulation produces a wide variety of Schwann cell phenotypes. Additionally, we found that Schwann cell phenotype is maintained for 2 weeks in vitro, demonstrating that it may survive several cell divisions without instructive cues from either axons or basal lamina.

  9. Diagnostic markers of axonal degeneration and demyelination in sensory nerve conduction.

    PubMed

    Oh, Shin J; Hemmi, Shoji; Hatanaka, Yuki

    2016-06-01

    The aim of this study was to formulate diagnostic hallmarks of axonal degeneration and demyelination in sensory nerve conduction studies (NCS). We compared nerve conduction data obtained with surface electrode (SE) NCS and on-nerve needle (ONN) NCS in 50 cases of demyelination and 22 cases of axonal degeneration as assessed by sural nerve biopsy. The overall diagnostic sensitivities of sensory nerve conduction were 26% by SE-NCS and 69% by ONN-NCS. The most helpful marker for demyelination was negative-peak nerve conduction velocity (NP-NCV), using a 36% decrease from the means in both techniques. Dispersion was also helpful in identifying demyelination. Low amplitude and absence of compound nerve action potential were indicative of general pathology in SE-NCS but of axonal degeneration in ONN-NCS. Although diagnostic sensitivity is low, NP-NCV and dispersion can be used for diagnosis of demyelination in sensory NCS. Muscle Nerve 53: 866-871, 2016. © 2015 Wiley Periodicals, Inc.

  10. Parkinson disease affects peripheral sensory nerves in the pharynx.

    PubMed

    Mu, Liancai; Sobotka, Stanislaw; Chen, Jingming; Su, Hungxi; Sanders, Ira; Nyirenda, Themba; Adler, Charles H; Shill, Holly A; Caviness, John N; Samanta, Johan E; Sue, Lucia I; Beach, Thomas G

    2013-07-01

    Dysphagia is very common in patients with Parkinson disease (PD) and often leads to aspiration pneumonia, the most common cause of death in PD. Current therapies are largely ineffective for dysphagia. Because pharyngeal sensation normally triggers the swallowing reflex, we examined pharyngeal sensory nerves in PD patients for Lewy pathology.Sensory nerves supplying the pharynx were excised from autopsied pharynges obtained from patients with clinically diagnosed and neuropathologically confirmed PD (n = 10) and healthy age-matched controls (n = 4). We examined the glossopharyngeal nerve (cranial nerve IX), the pharyngeal sensory branch of the vagus nerve (PSB-X), and the internal superior laryngeal nerve (ISLN) innervating the laryngopharynx. Immunohistochemistry for phosphorylated α-synuclein was used to detect Lewy pathology. Axonal α-synuclein aggregates in the pharyngeal sensory nerves were identified in all of the PD subjects but not in the controls. The density of α-synuclein-positive lesions was greater in PD patients with dysphagia versus those without dysphagia. In addition, α-synuclein-immunoreactive nerve fibers in the ISLN were much more abundant than those in cranial nerve IX and PSB-X. These findings suggest that pharyngeal sensory nerves are directly affected by pathologic processes in PD. These abnormalities may decrease pharyngeal sensation, thereby impairing swallowing and airway protective reflexes and contributing to dysphagia and aspiration.

  11. Parkinson Disease Affects Peripheral Sensory Nerves in the Pharynx

    PubMed Central

    Mu, Liancai; Sobotka, Stanislaw; Chen, Jingming; Su, Hungxi; Sanders, Ira; Nyirenda, Themba; Adler, Charles H.; Shill, Holly A.; Caviness, John N.; Samanta, Johan E.; Sue, Lucia I.; Beach, Thomas G.

    2013-01-01

    Dysphagia is very common in patients with Parkinson’s disease (PD) and often leads to aspiration pneumonia, the most common cause of death in PD. Unfortunately, current therapies are largely ineffective for dysphagia. As pharyngeal sensation normally triggers the swallowing reflex, we examined pharyngeal sensory nerves in PD for Lewy pathology. Sensory nerves supplying the pharynx were excised from autopsied pharynges obtained from patients with clinically diagnosed and neuropathologically confirmed PD (n = 10) and healthy age-matched controls (n = 4). We examined: the glossopharyngeal nerve (IX); the pharyngeal sensory branch of the vagus nerve (PSB-X); and the internal superior laryngeal nerve (ISLN) innervating the laryngopharynx. Immunohistochemistry for phosphorylated α-synuclein was used to detect potential Lewy pathology. Axonal α-synuclein aggregates in the pharyngeal sensory nerves were identified in all of the PD subjects but not in the controls. The density of α-synuclein-positive lesions was significantly greater in PD subjects with documented dysphagia compared to those without dysphagia. In addition, α-synuclein-immunoreactive nerve fibers in the ISLN were much more abundant than those in the IX and PSBX. These findings suggest that pharyngeal sensory nerves are directly affected by the pathologic process of PD. This anatomic pathology may decrease pharyngeal sensation impairing swallowing and airway protective reflexes, thereby contributing to dysphagia and aspiration. PMID:23771215

  12. Schwann Cell Expressed Nogo-B Modulates Axonal Branching of Adult Sensory Neurons Through the Nogo-B Receptor NgBR.

    PubMed

    Eckharter, Christoph; Junker, Nina; Winter, Lilli; Fischer, Irmgard; Fogli, Barbara; Kistner, Steffen; Pfaller, Kristian; Zheng, Binhai; Wiche, Gerhard; Klimaschewski, Lars; Schweigreiter, Rüdiger

    2015-01-01

    In contrast to the central nervous system (CNS) nerve fibers do regenerate in the peripheral nervous system (PNS) although in a clinically unsatisfying manner. A major problem is excessive sprouting of regenerating axons which results in aberrant reinnervation of target tissue and impaired functional recovery. In the CNS, the reticulon protein Nogo-A has been identified as a prominent oligodendrocyte expressed inhibitor of long-distance growth of regenerating axons. We show here that the related isoform Nogo-B is abundantly expressed in Schwann cells in the PNS. Other than Nogo-A in oligodendrocytes, Nogo-B does not localize to the myelin sheath but is detected in the ER and the plasma membrane of Schwann cells. Adult sensory neurons that are cultured on nogo-a/b deficient Schwann cells form significantly fewer axonal branches vs. those on wildtype Schwann cells, while their maximal axonal extension is unaffected. We demonstrate that this effect of Nogo-B on neuronal morphology is restricted to undifferentiated Schwann cells and is mediated by direct physical contact between these two cell types. Moreover, we show that blocking the Nogo-B specific receptor NgBR, which we find expressed on sensory neurons and to interact with Schwann cell expressed Nogo-B, produces the same branching phenotype as observed after deletion of Nogo-B. These data provide evidence for a novel function of the nogo gene that is implemented by the Nogo-B isoform. The remarkably specific effects of Nogo-B/NgBR on axonal branching, while leaving axonal extension unaffected, are of potential clinical relevance in the context of excessive axonal sprouting after peripheral nerve injury. Nogo-B is prominently expressed in Schwann cells and localizes to the ER and plasma membrane. It distributes to the external cytoplasmic compartment of Schwann cells in vivo, but is absent from the myelin sheath.Genetic deletion of Nogo-B in Schwann cells reduces axonal branching, but not long-distance growth, of

  13. Schwann Cell Expressed Nogo-B Modulates Axonal Branching of Adult Sensory Neurons Through the Nogo-B Receptor NgBR

    PubMed Central

    Eckharter, Christoph; Junker, Nina; Winter, Lilli; Fischer, Irmgard; Fogli, Barbara; Kistner, Steffen; Pfaller, Kristian; Zheng, Binhai; Wiche, Gerhard; Klimaschewski, Lars; Schweigreiter, Rüdiger

    2015-01-01

    In contrast to the central nervous system (CNS) nerve fibers do regenerate in the peripheral nervous system (PNS) although in a clinically unsatisfying manner. A major problem is excessive sprouting of regenerating axons which results in aberrant reinnervation of target tissue and impaired functional recovery. In the CNS, the reticulon protein Nogo-A has been identified as a prominent oligodendrocyte expressed inhibitor of long-distance growth of regenerating axons. We show here that the related isoform Nogo-B is abundantly expressed in Schwann cells in the PNS. Other than Nogo-A in oligodendrocytes, Nogo-B does not localize to the myelin sheath but is detected in the ER and the plasma membrane of Schwann cells. Adult sensory neurons that are cultured on nogo-a/b deficient Schwann cells form significantly fewer axonal branches vs. those on wildtype Schwann cells, while their maximal axonal extension is unaffected. We demonstrate that this effect of Nogo-B on neuronal morphology is restricted to undifferentiated Schwann cells and is mediated by direct physical contact between these two cell types. Moreover, we show that blocking the Nogo-B specific receptor NgBR, which we find expressed on sensory neurons and to interact with Schwann cell expressed Nogo-B, produces the same branching phenotype as observed after deletion of Nogo-B. These data provide evidence for a novel function of the nogo gene that is implemented by the Nogo-B isoform. The remarkably specific effects of Nogo-B/NgBR on axonal branching, while leaving axonal extension unaffected, are of potential clinical relevance in the context of excessive axonal sprouting after peripheral nerve injury. Main Points Nogo-B is prominently expressed in Schwann cells and localizes to the ER and plasma membrane. It distributes to the external cytoplasmic compartment of Schwann cells in vivo, but is absent from the myelin sheath. Genetic deletion of Nogo-B in Schwann cells reduces axonal branching, but not long

  14. [Immunoreactivity of the synapses on the primary afferent axons and sensory neurons of the spinal cord Lampetra fluviatilis].

    PubMed

    Adanina, V O; Rio, J P; Adanina, A S; Reperan, J; Veselkin, N P

    2008-01-01

    The existence of GABA-like immunoreactivity in the synapses on the primary afferent axons and GABA- and glutamate immunoreactive synapses on the dorsal cell somatic membrane was shown using double postembedding immunogold cytochemistry. These morphological findings suggest that control of the sensory information in the lamprey spinal cord is realized by means of presynaptic inhibition through the synapses on the primary afferent axons as well as directly through the synapses on the somata of the sensory neurons.

  15. A New Regulatory Mechanism for Kv7.2 Protein During Neuropathy: Enhanced Transport from the Soma to Axonal Terminals of Injured Sensory Neurons

    PubMed Central

    Cisneros, Elsa; Roza, Carolina; Jackson, Nieka; López-García, José Antonio

    2015-01-01

    Kv7.2 channel expression has been reported to decrease in dorsal root ganglia (DRG) following the induction of a peripheral neuropathy while other experiments show that Kv7.2 accumulates in peripheral neuromas. The mechanisms underlying these novel expression patterns are poorly understood. Here we use immunofluorescence methods to analyze Kv7.2 protein expression changes in sensory neurons following peripheral axotomy and the potential role of axonal transport. Results indicate that DRG neurons express Kv7.2 in ~16% of neurons and that this number decreases by about 65% after axotomy. Damaged neurons were identified in DRG by application of the tracer Fluoro-ruby at the site of injury during surgery. Reduction of Kv7.2 expression was particularly strong in damaged neurons although some loss was also found in putative uninjured neurons. In parallel to the decrease in the soma of axotomized sensory neurons, Kv7.2 accumulated at neuromatose fiber endings. Blockade of axonal transport with either vinblastine (VLB) or colchicine (COL) abolished Kv7.2 redistribution in neuropathic animals. Channel distribution rearrangements did not occur following induction of inflammation in the hind paw. Behavioral tests indicate that protein rearrangements within sensory afferents are essential to the development of allodynia under neuropathic conditions. These results suggest that axotomy enhances axonal transport in injured sensory neurons, leading to a decrease of somatic expression of Kv7.2 protein and a concomitant accumulation in damaged fiber endings. Localized changes in channel expression patterns under pathological conditions may create novel opportunities for Kv7.2 channel openers to act as analgesics. PMID:26696829

  16. Transfer of Vesicles From Schwann Cells to Axons: a Novel Mechanism of Communication in the Peripheral Nervous System

    PubMed Central

    Lopez-Verrilli, M. Alejandra; Court, Felipe A.

    2012-01-01

    Schwann cells (SCs) are the glial component of the peripheral nervous system, with essential roles during development and maintenance of axons, as well as during regenerative processes after nerve injury. SCs increase conduction velocities by myelinating axons, regulate synaptic activity at presynaptic nerve terminals and are a source of trophic factors to neurons. Thus, development and maintenance of peripheral nerves are crucially dependent on local signaling between SCs and axons. In addition to the classic mechanisms of intercellular signaling, the possibility of communication through secreted vesicles has been poorly explored to date. Interesting recent findings suggest the occurrence of lateral transfer mediated by vesicles from glial cells to axons that could have important roles in axonal growth and axonal regeneration. Here, we review the role of vesicular transfer from SCs to axons and propose the advantages of this means in supporting neuronal and axonal maintenance and regeneration after nerve damage. PMID:22707941

  17. Robo2 determines subtype-specific axonal projections of trigeminal sensory neurons

    PubMed Central

    Pan, Y. Albert; Choy, Margaret; Prober, David A.; Schier, Alexander F.

    2012-01-01

    How neurons connect to form functional circuits is central to the understanding of the development and function of the nervous system. In the somatosensory system, perception of sensory stimuli to the head requires specific connections between trigeminal sensory neurons and their many target areas in the central nervous system. Different trigeminal subtypes have specialized functions and downstream circuits, but it has remained unclear how subtype-specific axonal projection patterns are formed. Using zebrafish as a model system, we followed the development of two trigeminal sensory neuron subtypes: one that expresses trpa1b, a nociceptive channel important for sensing environmental chemicals; and a distinct subtype labeled by an islet1 reporter (Isl1SS). We found that Trpa1b and Isl1SS neurons have overall similar axon trajectories but different branching morphologies and distributions of presynaptic sites. Compared with Trpa1b neurons, Isl1SS neurons display reduced branch growth and synaptogenesis at the hindbrain-spinal cord junction. The subtype-specific morphogenesis of Isl1SS neurons depends on the guidance receptor Robo2. robo2 is preferentially expressed in the Isl1SS subset and inhibits branch growth and synaptogenesis. In the absence of Robo2, Isl1SS afferents acquire many of the characteristics of Trpa1b afferents. These results reveal that subtype-specific activity of Robo2 regulates subcircuit morphogenesis in the trigeminal sensory system. PMID:22190641

  18. Lithium Enhances Axonal Regeneration in Peripheral Nerve by Inhibiting Glycogen Synthase Kinase 3β Activation

    PubMed Central

    Su, Huanxing; Yuan, Qiuju; Qin, Dajiang; Yang, Xiaoying; So, Kwok-Fai; Wu, Wutian

    2014-01-01

    Brachial plexus injury often involves traumatic root avulsion resulting in permanent paralysis of the innervated muscles. The lack of sufficient regeneration from spinal motoneurons to the peripheral nerve (PN) is considered to be one of the major causes of the unsatisfactory outcome of various surgical interventions for repair of the devastating injury. The present study was undertaken to investigate potential inhibitory signals which influence axonal regeneration after root avulsion injury. The results of the study showed that root avulsion triggered GSK-3β activation in the injured motoneurons and remaining axons in the ventral funiculus. Systemic application of a clinical dose of lithium suppressed activated GSK-3β in the lesioned spinal cord to the normal level and induced extensive axonal regeneration into replanted ventral roots. Our study suggests that GSK-3β activity is involved in negative regulation for axonal elongation and regeneration and lithium, the specific GSK-3β inhibitor, enhances motoneuron regeneration from CNS to PNS. PMID:24967390

  19. Burning feet in polycythemia vera - peripheral sensorimotor axonal neuropathy with erythromelalgia.

    PubMed

    Wollina, Uwe

    2015-01-01

    Polycythemia vera is a rare myeloproliferative disease. Cutaneous symptoms are uncommon. We report about a 72-year-old female patient with JAK2(V617F) -positive polycythemia who developed peripheral sensorimotor axonal neuropathy and erythromelalgia. Possible causes and treatment are discussed.

  20. Combining peripheral nerve grafts and chondroitinase promotes functional axonal regeneration in the chronically injured spinal cord.

    PubMed

    Tom, Veronica J; Sandrow-Feinberg, Harra R; Miller, Kassi; Santi, Lauren; Connors, Theresa; Lemay, Michel A; Houlé, John D

    2009-11-25

    Because there currently is no treatment for spinal cord injury, most patients are living with long-standing injuries. Therefore, strategies aimed at promoting restoration of function to the chronically injured spinal cord have high therapeutic value. For successful regeneration, long-injured axons must overcome their poor intrinsic growth potential as well as the inhibitory environment of the glial scar established around the lesion site. Acutely injured axons that regenerate into growth-permissive peripheral nerve grafts (PNGs) reenter host tissue to mediate functional recovery if the distal graft-host interface is treated with chondroitinase ABC (ChABC) to cleave inhibitory chondroitin sulfate proteoglycans in the scar matrix. To determine whether a similar strategy is effective for a chronic injury, we combined grafting of a peripheral nerve into a highly relevant, chronic, cervical contusion site with ChABC treatment of the glial scar and glial cell line-derived neurotrophic factor (GDNF) stimulation of long-injured axons. We tested this combination in two grafting paradigms: (1) a peripheral nerve that was grafted to span a chronic injury site or (2) a PNG that bridged a chronic contusion site with a second, more distal injury site. Unlike GDNF-PBS treatment, GDNF-ChABC treatment facilitated axons to exit the PNG into host tissue and promoted some functional recovery. Electrical stimulation of axons in the peripheral nerve bridge induced c-Fos expression in host neurons, indicative of synaptic contact by regenerating fibers. Thus, our data demonstrate, for the first time, that administering ChABC to a distal graft interface allows for functional axonal regeneration by chronically injured neurons.

  1. Sensory map transfer to the neocortex relies on pretarget ordering of thalamic axons.

    PubMed

    Lokmane, Ludmilla; Proville, Rémi; Narboux-Nême, Nicolas; Györy, Ildiko; Keita, Maryama; Mailhes, Caroline; Léna, Clément; Gaspar, Patricia; Grosschedl, Rudolf; Garel, Sonia

    2013-05-06

    Sensory maps, such as the representation of mouse facial whiskers, are conveyed throughout the nervous system by topographic axonal projections that preserve neighboring relationships between adjacent neurons. In particular, the map transfer to the neocortex is ensured by thalamocortical axons (TCAs), whose terminals are topographically organized in response to intrinsic cortical signals. However, TCAs already show a topographic order early in development, as they navigate toward their target. Here, we show that this preordering of TCAs is required for the transfer of the whisker map to the neocortex. Using Ebf1 conditional inactivation that specifically perturbs the development of an intermediate target, the basal ganglia, we scrambled TCA topography en route to the neocortex without affecting the thalamus or neocortex. Notably, embryonic somatosensory TCAs were shifted toward the visual cortex and showed a substantial intermixing along their trajectory. Somatosensory TCAs rewired postnatally to reach the somatosensory cortex but failed to form a topographic anatomical or functional map. Our study reveals that sensory map transfer relies not only on positional information in the projecting and target structures but also on preordering of axons along their trajectory, thereby opening novel perspectives on brain wiring.

  2. Increased Cx32 expression in spinal cord TrkB oligodendrocytes following peripheral axon injury.

    PubMed

    Coulibaly, Aminata P; Isaacson, Lori G

    2016-08-03

    Following injury to motor axons in the periphery, retrograde influences from the injury site lead to glial cell plasticity in the vicinity of the injured neurons. Following the transection of peripherally located preganglionic axons of the cervical sympathetic trunk (CST), a population of oligodendrocyte (OL) lineage cells expressing full length TrkB, the cognate receptor for brain derived neurotrophic factor (BDNF), is significantly increased in number in the spinal cord. Such robust plasticity in OL lineage cells in the spinal cord following peripheral axon transection led to the hypothesis that the gap junction communication protein connexin 32 (Cx32), which is specific to OL lineage cells, was influenced by the injury. Following CST transection, Cx32 expression in the spinal cord intermediolateral cell column (IML), the location of the parent cell bodies, was significantly increased. The increased Cx32 expression was localized specifically to TrkB OLs in the IML, rather than other cell types in the OL cell lineage, with the population of Cx32/TrkB cells increased by 59%. Cx32 expression in association with OPCs was significantly decreased at one week following the injury. The results of this study provide evidence that peripheral axon injury can differentially affect the gap junction protein expression in OL lineage cells in the adult rat spinal cord. We conclude that the retrograde influences originating from the peripheral injury site elicit dramatic changes in the CNS expression of Cx32, which in turn may mediate the plasticity of OL lineage cells observed in the spinal cord following peripheral axon injury.

  3. Role of macrophages in Wallerian degeneration and axonal regeneration after peripheral nerve injury.

    PubMed

    Chen, Peiwen; Piao, Xianhua; Bonaldo, Paolo

    2015-11-01

    The peripheral nervous system (PNS) has remarkable regenerative abilities after injury. Successful PNS regeneration relies on both injured axons and non-neuronal cells, including Schwann cells and immune cells. Macrophages are the most notable immune cells that play key roles in PNS injury and repair. Upon peripheral nerve injury, a large number of macrophages are accumulated at the injury sites, where they not only contribute to Wallerian degeneration, but also are educated by the local microenvironment and polarized to an anti-inflammatory phenotype (M2), thus contributing to axonal regeneration. Significant progress has been made in understanding how macrophages are educated and polarized in the injured microenvironment as well as how they contribute to axonal regeneration. Following the discussion on the main properties of macrophages and their phenotypes, in this review, we will summarize the current knowledge regarding the mechanisms of macrophage infiltration after PNS injury. Moreover, we will discuss the recent findings elucidating how macrophages are polarized to M2 phenotype in the injured PNS microenvironment, as well as the role and underlying mechanisms of macrophages in peripheral nerve injury, Wallerian degeneration and regeneration. Furthermore, we will highlight the potential application by targeting macrophages in treating peripheral nerve injury and peripheral neuropathies.

  4. Upslope treadmill exercise enhances motor axon regeneration but not functional recovery following peripheral nerve injury

    PubMed Central

    Cannoy, Jill; Crowley, Sam; Jarratt, Allen; Werts, Kelly LeFevere; Osborne, Krista; Park, Sohee

    2016-01-01

    Following peripheral nerve injury, moderate daily exercise conducted on a level treadmill results in enhanced axon regeneration and modest improvements in functional recovery. If the exercise is conducted on an upwardly inclined treadmill, even more motor axons regenerate successfully and reinnervate muscle targets. Whether this increased motor axon regeneration also results in greater improvement in functional recovery from sciatic nerve injury was studied. Axon regeneration and muscle reinnervation were studied in Lewis rats over an 11 wk postinjury period using stimulus evoked electromyographic (EMG) responses in the soleus muscle of awake animals. Motor axon regeneration and muscle reinnervation were enhanced in slope-trained rats. Direct muscle (M) responses reappeared faster in slope-trained animals than in other groups and ultimately were larger than untreated animals. The amplitude of monosynaptic H reflexes recorded from slope-trained rats remained significantly smaller than all other groups of animals for the duration of the study. The restoration of the amplitude and pattern of locomotor EMG activity in soleus and tibialis anterior and of hindblimb kinematics was studied during treadmill walking on different slopes. Slope-trained rats did not recover the ability to modulate the intensity of locomotor EMG activity with slope. Patterned EMG activity in flexor and extensor muscles was not noted in slope-trained rats. Neither hindblimb length nor limb orientation during level, upslope, or downslope walking was restored in slope-trained rats. Slope training enhanced motor axon regeneration but did not improve functional recovery following sciatic nerve transection and repair. PMID:27466130

  5. Ixabepilone-induced mitochondria and sensory axon loss in breast cancer patients

    PubMed Central

    Ebenezer, Gigi J; Carlson, Karen; Donovan, Diana; Cobham, Marta; Chuang, Ellen; Moore, Anne; Cigler, Tessa; Ward, Maureen; Lane, Maureen E; Ramnarain, Anita; Vahdat, Linda T; Polydefkis, Michael

    2014-01-01

    Background We sought to define the clinical and ultrastructure effects of ixabepilone (Ix), a microtubule-stabilizing chemotherapy agent on cutaneous sensory nerves and to investigate a potential mitochondrial toxicity mechanism. Methods Ten breast cancer patients receiving Ix underwent total neuropathy score clinical (TNSc) assessment, distal leg skin biopsies at cycle (Cy) 3 (80–90 mg/m2), Cy5 (160–190 mg/m2), and Cy7 (>200 mg/m2) and were compared to 5 controls. Skin blocks were processed for EM and ultrastructural morphometry of Remak axons done. Results At baseline, Ix-treated subjects had higher TNSc values (4.5 ± 0.8 vs. 0.0 ± 0.0), greater percentage of empty (denervated) Schwann cells (29% vs. 12%), altered axonal diameter (422.9 ± 17 vs. 354.9 ± 14.8 nm, P = 0.01), and axon profiles without mitochondria tended to increase compared to control subjects (71% vs. 70%). With increasing cumulative Ix exposure, an increase in TNSc values (Cy3: 5.4 ± 1.2, Cy7: 10 ± 4, P < 0.001), empty Schwann cells (39% by Cy7), and dilated axons (in nm, Cy3: 506.3 ± 22.1, Cy5: 534.8 ± 33, Cy7: 527.8 ± 24.4; P < 0.001) was observed. In addition, axon profiles without mitochondria (Cy3:74%, Cy7:78%) and mitochondria with abnormal morphology (grade 3 or 4) increased from 24% to 79%. Schwann cells with atypical mitochondria and perineuronal macrophage infiltration in dermis were noted. Interpretation This study provides functional and structural evidence that Ix exposure induces a dose-dependent toxicity on small sensory fibers with an increase in TNSc scores and progressive axonal loss. Mitochondria appear to bear the cumulative toxic effect and chemotherapy-induced toxicity can be monitored through serial skin biopsy-based analysis. PMID:25493278

  6. Role of competition among sensory neurons in regulation of pattern of innervation at their central and peripheral targets.

    PubMed

    Mendelson, B; Frank, E

    1989-11-01

    1. The importance of competitive interactions among muscle sensory afferents on their projections to central and peripheral targets was studied by producing large reductions in the number of afferents during development. Removal of the brachial dorsal root ganglion (DRG2), which normally supplies the entire sensory innervation of the forelimb, in bullfrog (Rana catesbeiana) tadpoles caused a smaller number of neurons in the adjacent thoracic ganglion (DRG3) to sprout into the forelimb and into the brachial spinal cord. 2. Horseradish peroxidase labeling in postmetamorphic animals showed that DRG3 neurons innervating the triceps muscle arborize in a novel but now appropriate area of the spinal cord, the region containing motoneuronal dendrites. These foreign afferents do not arborize in inappropriate regions of the spinal gray matter, and their collaterals have the same rostrocaudal distribution as those of normal DRG2 muscle afferents. 3. After metamorphosis, the number of DRG3 sensory axons in individual triceps muscle nerves was determined. Normally, two-thirds of all triceps afferents project to the medial head alone, even though each of the three heads is of similar size and is contacted by similar numbers of motoneurons. After DRG2 removal, although the total number of DRG3 afferents projecting to the triceps muscle was smaller than normal, the medial head still received approximately two-thirds of the axons, just as in normal frogs. These results suggest that the proportional sensory innervation of the triceps muscle-heads is not dependent on competitive interactions among afferents. 4. DRG3 afferents projecting to the forelimb also sprouted to innervate appropriate brachial motoneurons. The average strength of connection between individual sensory and motor neurons was found to be the same as in normal animals, even though there was presumably more central target space available for each afferent axon. This suggests that the number and/or strength of central

  7. Axon-Schwann cell interactions during peripheral nerve regeneration in zebrafish larvae

    PubMed Central

    2014-01-01

    Background Peripheral nerve injuries can severely affect the way that animals perceive signals from the surrounding environment. While damage to peripheral axons generally has a better outcome than injuries to central nervous system axons, it is currently unknown how neurons re-establish their target innervations to recover function after injury, and how accessory cells contribute to this task. Here we use a simple technique to create reproducible and localized injury in the posterior lateral line (pLL) nerve of zebrafish and follow the fate of both neurons and Schwann cells. Results Using pLL single axon labeling by transient transgene expression, as well as transplantation of glial precursor cells in zebrafish larvae, we individualize different components in this system and characterize their cellular behaviors during the regenerative process. Neurectomy is followed by loss of Schwann cell differentiation markers that is reverted after nerve regrowth. We show that reinnervation of lateral line hair cells in neuromasts during pLL nerve regeneration is a highly dynamic process with promiscuous yet non-random target recognition. Furthermore, Schwann cells are required for directional extension and fasciculation of the regenerating nerve. We provide evidence that these cells and regrowing axons are mutually dependant during early stages of nerve regeneration in the pLL. The role of ErbB signaling in this context is also explored. Conclusion The accessibility of the pLL nerve and the availability of transgenic lines that label this structure and their synaptic targets provides an outstanding in vivo model to study the different events associated with axonal extension, target reinnervation, and the complex cellular interactions between glial cells and injured axons during nerve regeneration. PMID:25326036

  8. Acute motor-sensory axonal neuropathy associated with active systemic lupus erythematosus and anticardiolipin antibodies.

    PubMed

    Ubogu, E E; Zaidat, O O; Suarez, J I

    2001-10-01

    Acute motor-sensory axonal neuropathy (AMSAN) is an axonal variant of Guillian-Barré syndrome (GBS) that presents with acute ascending quadriparesis. This has generally been described in association with Campylobacter jejuni infections or with anti-ganglioside antibodies. Known cases have shown a slow recovery and a poor prognosis. We report a case with clinical and electrophysiological evidence of AMSAN in association with active systemic lupus erythematosus (SLE) and anticardiolipin antibodies but not the other associations, with a rapid response to combination immunosuppressant and intravenous immunoglobulin (IVIg) therapy. The association between AMSAN and SLE has not been previously described. This case illustrates that early recognition and the utilization of electrophysiologic techniques may be beneficial in the diagnosis and management of GBS associated with SLE. Fulminant or rapidly progressive cases should be managed in specialized intensive care units. Combination therapy of immunosuppressants and IVIg may be beneficial in non-vasculitic axonal radiculo-neuropathies associated with SLE, resulting in good outcomes.

  9. A Mechanistic Understanding of Axon Degeneration in Chemotherapy-Induced Peripheral Neuropathy

    PubMed Central

    Fukuda, Yusuke; Li, Yihang; Segal, Rosalind A.

    2017-01-01

    Chemotherapeutic agents cause many short and long term toxic side effects to peripheral nervous system (PNS) that drastically alter quality of life. Chemotherapy-induced peripheral neuropathy (CIPN) is a common and enduring disorder caused by several anti-neoplastic agents. CIPN typically presents with neuropathic pain, numbness of distal extremities, and/or oversensitivity to thermal or mechanical stimuli. This adverse side effect often requires a reduction in chemotherapy dosage or even discontinuation of treatment. Currently there are no effective treatment options for CIPN. While the underlying mechanisms for CIPN are not understood, current data identify a “dying back” axon degeneration of distal nerve endings as the major pathology in this disorder. Therefore, mechanistic understanding of axon degeneration will provide insights into the pathway and molecular players responsible for CIPN. Here, we review recent findings that expand our understanding of the pathogenesis of CIPN and discuss pathways that may be shared with the axonal degeneration that occurs during developmental axon pruning and during injury-induced Wallerian degeneration. These mechanistic insights provide new avenues for development of therapies to prevent or treat CIPN. PMID:28912674

  10. Involvement of ADAM10 in axonal outgrowth and myelination of the peripheral nerve.

    PubMed

    Jangouk, Parastoo; Dehmel, Thomas; Meyer Zu Hörste, Gerd; Ludwig, Andreas; Lehmann, Helmar C; Kieseier, Bernd C

    2009-12-01

    The disintegrin and metalloproteinase 10 (ADAM10) is a membrane-anchored metalloproteinase with both proteolytic and disintegrin characteristics. Here, we investigate the expression, regulation, and functional role of ADAM10 in axonal outgrowth and myelination of the peripheral nerve. Expression pattern analysis of 11 ADAM family members in co-cultures of rat dorsal root ganglia (DRG) neurons and Schwann cells (SCs) demonstrated the most pronounced mRNA expression for ADAM10. In further studies, ADAM10 was found to be consistently upregulated in DRG-SC co-cultures before the induction of myelination. Neurons as well as SCs widely expressed ADAM10 at the protein level. In neurons, the expression of ADAM10 was exclusively limited to the axons before the induction of myelination. Inhibition of ADAM10 activity by the hydroxamate-based inhibitors GI254023X and GW280264X resulted in a significant decrease in the mean axonal length. These data suggest that ADAM10 represents a prerequisite for myelination, although its activity is not required during the process of myelination itself as demonstrated by expression analysis of myelin protein zero (P0) and Sudan black staining. Hence, during the process of myelin formation, ADAM10 is highly upregulated and appears to be critically involved in axonal outgrowth that is a requirement for myelination in the peripheral nerve.

  11. A Mechanistic Understanding of Axon Degeneration in Chemotherapy-Induced Peripheral Neuropathy.

    PubMed

    Fukuda, Yusuke; Li, Yihang; Segal, Rosalind A

    2017-01-01

    Chemotherapeutic agents cause many short and long term toxic side effects to peripheral nervous system (PNS) that drastically alter quality of life. Chemotherapy-induced peripheral neuropathy (CIPN) is a common and enduring disorder caused by several anti-neoplastic agents. CIPN typically presents with neuropathic pain, numbness of distal extremities, and/or oversensitivity to thermal or mechanical stimuli. This adverse side effect often requires a reduction in chemotherapy dosage or even discontinuation of treatment. Currently there are no effective treatment options for CIPN. While the underlying mechanisms for CIPN are not understood, current data identify a "dying back" axon degeneration of distal nerve endings as the major pathology in this disorder. Therefore, mechanistic understanding of axon degeneration will provide insights into the pathway and molecular players responsible for CIPN. Here, we review recent findings that expand our understanding of the pathogenesis of CIPN and discuss pathways that may be shared with the axonal degeneration that occurs during developmental axon pruning and during injury-induced Wallerian degeneration. These mechanistic insights provide new avenues for development of therapies to prevent or treat CIPN.

  12. In vivo testing of a 3D bifurcating microchannel scaffold inducing separation of regenerating axon bundles in peripheral nerves

    NASA Astrophysics Data System (ADS)

    Stoyanova, Irina I.; van Wezel, Richard J. A.; Rutten, Wim L. C.

    2013-12-01

    Artificial nerve guidance channels enhance the regenerative effectiveness in an injured peripheral nerve but the existing design so far has been limited to basic straight tubes simply guiding the growth to bridge the gap. Hence, one of the goals in development of more effective neuroprostheses is to create bidirectional highly selective neuro-electronic interface between a prosthetic device and the severed nerve. A step towards improving selectivity for both recording and stimulation have been made with some recent in vitro studies which showed that three-dimensional (3D) bifurcating microchannels can separate neurites growing on a planar surface and bring them into contact with individual electrodes. Since the growing axons in vivo have the innate tendency to group in bundles surrounded by connective tissue, one of the big challenges in neuro-prosthetic interface design is how to overcome it. Therefore, we performed experiments with 3D bifurcating guidance scaffolds implanted in the sciatic nerve of rats to test if this new channel architecture could trigger separation pattern of ingrowth also in vivo. Our results showed that this new method enabled the re-growth of neurites into channels with gradually diminished width (80, 40 and 20 µm) and facilitated the separation of the axonal bundles with 91% success. It seems that the 3D bifurcating scaffold might contribute towards conveying detailed neural control and sensory feedback to users of prosthetic devices, and thus could improve the quality of their daily life.

  13. Peroxisomal dysfunctions cause lysosomal storage and axonal Kv1 channel redistribution in peripheral neuropathy

    PubMed Central

    Kleinecke, Sandra; Richert, Sarah; de Hoz, Livia; Brügger, Britta; Kungl, Theresa; Asadollahi, Ebrahim; Quintes, Susanne; Blanz, Judith; McGonigal, Rhona; Naseri, Kobra; Sereda, Michael W; Sachsenheimer, Timo; Lüchtenborg, Christian; Möbius, Wiebke; Willison, Hugh; Baes, Myriam; Nave, Klaus-Armin; Kassmann, Celia Michèle

    2017-01-01

    Impairment of peripheral nerve function is frequent in neurometabolic diseases, but mechanistically not well understood. Here, we report a novel disease mechanism and the finding that glial lipid metabolism is critical for axon function, independent of myelin itself. Surprisingly, nerves of Schwann cell-specific Pex5 mutant mice were unaltered regarding axon numbers, axonal calibers, and myelin sheath thickness by electron microscopy. In search for a molecular mechanism, we revealed enhanced abundance and internodal expression of axonal membrane proteins normally restricted to juxtaparanodal lipid-rafts. Gangliosides were altered and enriched within an expanded lysosomal compartment of paranodal loops. We revealed the same pathological features in a mouse model of human Adrenomyeloneuropathy, preceding disease-onset by one year. Thus, peroxisomal dysfunction causes secondary failure of local lysosomes, thereby impairing the turnover of gangliosides in myelin. This reveals a new aspect of axon-glia interactions, with Schwann cell lipid metabolism regulating the anchorage of juxtaparanodal Kv1-channels. DOI: http://dx.doi.org/10.7554/eLife.23332.001 PMID:28470148

  14. Mammalian Target of Rapamycin (mTOR) Activation Increases Axonal Growth Capacity of Injured Peripheral Nerves*

    PubMed Central

    Abe, Namiko; Borson, Steven H.; Gambello, Michael J.; Wang, Fan; Cavalli, Valeria

    2010-01-01

    Unlike neurons in the central nervous system (CNS), injured neurons in the peripheral nervous system (PNS) can regenerate their axons and reinnervate their targets. However, functional recovery in the PNS often remains suboptimal, especially in cases of severe damage. The lack of regenerative ability of CNS neurons has been linked to down-regulation of the mTOR (mammalian target of rapamycin) pathway. We report here that PNS dorsal root ganglial neurons (DRGs) activate mTOR following damage and that this activity enhances axonal growth capacity. Furthermore, genetic up-regulation of mTOR activity by deletion of tuberous sclerosis complex 2 (TSC2) in DRGs is sufficient to enhance axonal growth capacity in vitro and in vivo. We further show that mTOR activity is linked to the expression of GAP-43, a crucial component of axonal outgrowth. However, although TSC2 deletion in DRGs facilitates axonal regrowth, it leads to defects in target innervation. Thus, whereas manipulation of mTOR activity could provide new strategies to stimulate nerve regeneration in the PNS, fine control of mTOR activity is required for proper target innervation. PMID:20615870

  15. Axon Growth and Guidance Genes Identify Nascent, Immature, and Mature Olfactory Sensory Neurons

    PubMed Central

    McIntyre, Jeremy C.; Titlow, William B.; McClintock, Timothy S.

    2016-01-01

    Neurogenesis of projection neurons requires that axons be initiated, extended, and connected. Differences in the expression of axon growth and guidance genes must drive these events, but comprehensively characterizing these differences in a single neuronal type has not been accomplished. Guided by a catalog of gene expression in olfactory sensory neurons (OSNs), in situ hybridization and immunohistochemistry revealed that Cxcr4 and Dbn1, two axon initiation genes, marked the developmental transition from basal progenitor cells to immature OSNs in the olfactory epithelium. The CXCR4 immunoreactivity of these nascent OSNs overlapped partially with markers of proliferation of basal progenitor cells and partially with immunoreactivity for GAP43, the canonical marker of immature OSNs. Intracellular guidance cue signaling transcripts Ablim1, Crmp1, Dypsl2, Dpysl3, Dpysl5, Gap43, Marcskl1, and Stmn1–4 were specific to, or much more abundant in, the immature OSN layer. Receptors that mediate axonal inhibition or repulsion tended to be expressed in both immature and mature OSNs (Plxna1, Plxna4, Nrp2, Efna5) or specifically in mature OSNs (Plxna3, Unc5b, Efna3, Epha5, Epha7), although some were specific to immature OSNs (Plxnb1, Plxnb2, Plxdc2, Nrp1). Cell adhesion molecules were expressed either by both immature and mature OSNs (Dscam, Ncam1, Ncam2, Nrxn1) or solely by immature OSNs (Chl1, Nfasc1, Dscaml1). Given the loss of intracellular signaling protein expression, the continued expression of guidance cue receptors in mature OSNs is consistent with a change in the role of these receptors, perhaps to sending signals back to the cell body and nucleus. PMID:20882566

  16. Attractant and repellent cues cooperate in guiding a subset of olfactory sensory axons to a well-defined protoglomerular target.

    PubMed

    Taku, Alemji A; Marcaccio, Christina L; Ye, Wenda; Krause, Gregory J; Raper, Jonathan A

    2016-01-01

    Olfactory sensory axons target well-defined intermediate targets in the zebrafish olfactory bulb called protoglomeruli well before they form odorant receptor-specific glomeruli. A subset of olfactory sensory neurons are labeled by expression of the or111-7:IRES:GAL4 transgene whose axons terminate in the central zone (CZ) protoglomerulus. Previous work has shown that some of these axons misproject to the more dorsal and anterior dorsal zone (DZ) protoglomerulus in the absence of Netrin 1/Dcc signaling. In search of additional cues that guide these axons to the CZ, we found that Semaphorin 3D (Sema3D) is expressed in the anterior bulb and acts as a repellent that pushes them towards the CZ. Further analysis indicates that Sema3D signaling is mediated through Nrp1a, while Nrp2b also promotes CZ targeting but in a Sema3D-independent manner. nrp1a, nrp2b and dcc transcripts are detected in or111-7 transgene-expressing neurons early in development and both Nrp1a and Dcc act cell-autonomously in sensory neurons to promote accurate targeting to the CZ. dcc and nrp1a double mutants have significantly more DZ misprojections than either single mutant, suggesting that the two signaling systems act independently and in parallel to direct a specific subset of sensory axons to their initial protoglomerular target.

  17. Attractant and repellent cues cooperate in guiding a subset of olfactory sensory axons to a well-defined protoglomerular target

    PubMed Central

    Taku, Alemji A.; Marcaccio, Christina L.; Ye, Wenda; Krause, Gregory J.; Raper, Jonathan A.

    2016-01-01

    Olfactory sensory axons target well-defined intermediate targets in the zebrafish olfactory bulb called protoglomeruli well before they form odorant receptor-specific glomeruli. A subset of olfactory sensory neurons are labeled by expression of the or111-7:IRES:GAL4 transgene whose axons terminate in the central zone (CZ) protoglomerulus. Previous work has shown that some of these axons misproject to the more dorsal and anterior dorsal zone (DZ) protoglomerulus in the absence of Netrin 1/Dcc signaling. In search of additional cues that guide these axons to the CZ, we found that Semaphorin 3D (Sema3D) is expressed in the anterior bulb and acts as a repellent that pushes them towards the CZ. Further analysis indicates that Sema3D signaling is mediated through Nrp1a, while Nrp2b also promotes CZ targeting but in a Sema3D-independent manner. nrp1a, nrp2b and dcc transcripts are detected in or111-7 transgene-expressing neurons early in development and both Nrp1a and Dcc act cell-autonomously in sensory neurons to promote accurate targeting to the CZ. dcc and nrp1a double mutants have significantly more DZ misprojections than either single mutant, suggesting that the two signaling systems act independently and in parallel to direct a specific subset of sensory axons to their initial protoglomerular target. PMID:26732841

  18. Evidence of GLP-1-mediated neuroprotection in an animal model of pyridoxine-induced peripheral sensory neuropathy

    PubMed Central

    Perry, TracyAnn; Holloway, Harold W.; Weerasuriya, Ananda; Mouton, Peter R.; Duffy, Kara; Mattison, Julie A.; Greig, Nigel H.

    2007-01-01

    Pyridoxine (vitamin B6) intoxicated rodents develop a peripheral neuropathy characterized by sensory nerve conduction deficits associated with disturbances of nerve fiber geometry and axonal atrophy. To investigate the possibility that glucagon-like peptide-1 (7-36)-amide (GLP-1) receptor agonism may influence axonal structure and function through neuroprotection neurotrophic support, effects of GLP-1 and its long acting analog, Exendin-4 (Ex4) treatment on pyridoxine-induced peripheral neuropathy were examined in rats using behavioral and morphometric techniques. GLP-1 is an endogenous insulinotropic peptide secreted from the gut in response to the presence of food. GLP-1 receptors (GLP-1R) are coupled to the cAMP second messenger pathway, and are expressed widely throughout neural tissues of humans and rodents. Recent studies have established that GLP-1 and Ex4, have multiple synergistic effects on glucose-dependent insulin secretion pathways of pancreatic β-cells and on neural plasticity. Data reported here suggest that clinically relevant doses of GLP-1 and Ex4 may offer some protection against the sensory peripheral neuropathy induced by pyridoxine. Our findings suggest a potential role for these peptides in the treatment of neuropathies, including that associated with type II diabetes mellitus. PMID:17125767

  19. Low-density Lipoprotein Receptor-related Proteins in a Novel Mechanism of Axon Guidance and Peripheral Nerve Regeneration.

    PubMed

    Landowski, Lila M; Pavez, Macarena; Brown, Lachlan S; Gasperini, Robert; Taylor, Bruce V; West, Adrian K; Foa, Lisa

    2016-01-15

    The low-density lipoprotein receptor-related protein receptors 1 and 2 (LRP1 and LRP2) are emerging as important cell signaling mediators in modulating neuronal growth and repair. We examined whether LRP1 and LRP2 are able to mediate a specific aspect of neuronal growth: axon guidance. We sought to identify LRP1 and LRP2 ligands that could induce axonal chemoattraction, which might have therapeutic potential. Using embryonic sensory neurons (rat dorsal root ganglia) in a growth cone turning assay, we tested a range of LRP1 and LRP2 ligands for the ability to guide growth cone navigation. Three ligands were chemorepulsive: α-2-macroglobulin, tissue plasminogen activator, and metallothionein III. Conversely, only one LRP ligand, metallothionein II, was found to be chemoattractive. Chemoattraction toward a gradient of metallothionein II was calcium-dependent, required the expression of both LRP1 and LRP2, and likely involves further co-receptors such as the tropomyosin-related kinase A (TrkA) receptor. The potential for LRP-mediated chemoattraction to mediate axonal regeneration was examined in vivo in a model of chemical denervation in adult rats. In these in vivo studies, metallothionein II was shown to enhance epidermal nerve fiber regeneration so that it was complete within 7 days compared with 14 days in saline-treated animals. Our data demonstrate that both LRP1 and LRP2 are necessary for metallothionein II-mediated chemotactic signal transduction and that they may form part of a signaling complex. Furthermore, the data suggest that LRP-mediated chemoattraction represents a novel, non-classical signaling system that has therapeutic potential as a disease-modifying agent for the injured peripheral nervous system.

  20. Effects of eribulin, vincristine, paclitaxel and ixabepilone on fast axonal transport and kinesin-1 driven microtubule gliding: Implications for chemotherapy-induced peripheral neuropathy

    PubMed Central

    LaPointe, Nichole E.; Morfini, Gerardo; Brady, Scott T.; Feinstein, Stuart C.; Wilson, Leslie; Jordan, Mary Ann

    2014-01-01

    Chemotherapy-induced peripheral neuropathy (CIPN) is a serious, painful and dose-limiting side effect of cancer drugs that target microtubules. The mechanisms underlying the neuronal damage are unknown, but may include disruption of fast axonal transport, an essential microtubule-based process that moves cellular components over long distances between neuronal cell bodies and nerve terminals. This idea is supported by the “dying back” pattern of degeneration observed in CIPN, and by the selective vulnerability of sensory neurons bearing the longest axonal projections. In this study, we test the hypothesis that microtubule-targeting drugs disrupt fast axonal transport using vesicle motility assays in isolated squid axoplasm and a cell-free microtubule gliding assay with defined components. We compare four clinically-used drugs, eribulin, vincristine, paclitaxel and ixabepilone. Of these, eribulin is associated with a relatively low incidence of severe neuropathy, while vincristine has a relatively high incidence. In vesicle motility assays, we found that all four drugs inhibited anterograde (conventional kinesin-dependent) fast axonal transport, with the potency being vincristine = ixabepilone > paclitaxel = eribulin. Interestingly, eribulin and paclitaxel did not inhibit retrograde (cytoplasmic dynein-dependent) fast axonal transport, in contrast to vincristine and ixabepilone. Similarly, vincristine and ixabepilone both exerted significant inhibitory effects in an in vitro microtubule gliding assay consisting of recombinant kinesin (kinesin-1) and microtubules composed of purified bovine brain tubulin, whereas paclitaxel and eribulin had negligible effects. Our results suggest that (i) inhibition of microtubule-based fast axonal transport may be a significant contributor to neurotoxicity induced by microtubule-targeting drugs, and (ii) that individual microtubule-targeting drugs affect fast axonal transport through different mechanisms. PMID:23711742

  1. gp130 cytokines are positive signals triggering changes in gene expression and axon outgrowth in peripheral neurons following injury

    PubMed Central

    Zigmond, Richard E.

    2012-01-01

    Adult peripheral neurons, in contrast to adult central neurons, are capable of regeneration after axonal damage. Much attention has focused on the changes that accompany this regeneration in two places, the distal nerve segment (where phagocytosis of axonal debris, changes in the surface properties of Schwann cells, and induction of growth factors and cytokines occur) and the neuronal cell body (where dramatic changes in cell morphology and gene expression occur). The changes in the axotomized cell body are often referred to as the “cell body response.” The focus of the current review is a family of cytokines, the glycoprotein 130 (gp130) cytokines, which produce their actions through a common gp130 signaling receptor and which function as injury signals for axotomized peripheral neurons, triggering changes in gene expression and in neurite outgrowth. These cytokines play important roles in the responses of sympathetic, sensory, and motor neurons to injury. The best studied of these cytokines in this context are leukemia inhibitory factor (LIF) and interleukin (IL)-6, but experiments with conditional gp130 knockout animals suggest that other members of this family, not yet determined, are also involved. The primary gp130 signaling pathway shown to be involved is the activation of Janus kinase (JAK) and the transcription factors Signal Transducers and Activators of Transcription (STAT), though other downstream pathways such as mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) may also play a role. gp130 signaling may involve paracrine, retrograde, and autocrine actions of these cytokines. Recent studies suggest that manipulation of this cytokine system can also stimulate regeneration by injured central neurons. PMID:22319466

  2. Roundabout gene family functions during sensory axon guidance in the drosophila embryo are mediated by both Slit-dependent and Slit-independent mechanisms.

    PubMed

    Parsons, Linda; Harris, Kerri-Lee; Turner, Kirsty; Whitington, Paul M

    2003-12-15

    roundabout (robo) family genes play key roles in axon guidance in a wide variety of animals. We have investigated the roles of the robo family members, robo, robo2, and robo3, in the guidance of sensory axons in the Drosophila embryo. In robo(-/-), slit(-/-), and robo(-/+) slit(-/+) mutants, lateral cluster sensory neurons misproject to cells and axons in the nearby ventral' (v') cluster. These phenotypes, together with the normal expression pattern of Slit and Robo, suggest that Slit ligand secreted from the epidermis interacts with Robo receptors on lateral cluster sensory growth cones to limit their exploration of nearby attractive substrates. The most common sensory axon phenotype seen in robo2(-/-) mutants was misprojection of dorsal cluster sensory axons away from their normal growth substrate, the transverse connective of the trachea. slit appears to play no role in this aspect of sensory axon growth. Robo2 is expressed, not on the dorsal sensory axons, but on the transverse connective. These results suggest a novel, non-cell-autonomous mechanism for axon guidance by robo family genes: Robo2 expressed on the trachea acts as an attractant for the dorsal sensory growth cones.

  3. Berberine promotes axonal regeneration in injured nerves of the peripheral nervous system.

    PubMed

    Han, Ah Mi; Heo, Hwon; Kwon, Yunhee Kim

    2012-04-01

    Berberine, an isoquinoline alkaloid component of Coptidis Rhizoma (goldenthread) extract, has been reported to have therapeutic potential for central nervous system disorders such as Alzheimer's disease, cerebral ischemia, and schizophrenia. We have previously shown that berberine promotes the survival and differentiation of hippocampal precursor cells. In a memory-impaired rat model induced by ibotenic acid injection, the survival of pyramidal and granular cells was greatly increased in the hippocampus by berberine administration. In the present study, we investigated the effects of berberine on neurite outgrowth in the SH-SY5Y neuronal cell line and axonal regeneration in the rat peripheral nervous system (PNS). Berberine enhanced neurite extension in differentiating SH-SY5Y cells at concentrations of 0.25-3 μg/mL. In an injury model of the rat sciatic nerve, we examined the neuroregenerative effects of berberine on axonal remyelination by using immunohistochemical analysis. Four weeks after berberine administration (20 mg/kg i.p. once per day for 1 week), the thickness of remyelinated axons improved approximately 1.4-fold in the distal stump of the injury site. Taken together, these results indicate that berberine promotes neurite extension and axonal regeneration in injured nerves of the PNS.

  4. A regenerative microchannel neural interface for recording from and stimulating peripheral axons in vivo

    NASA Astrophysics Data System (ADS)

    FitzGerald, James J.; Lago, Natalia; Benmerah, Samia; Serra, Jordi; Watling, Christopher P.; Cameron, Ruth E.; Tarte, Edward; Lacour, Stéphanie P.; McMahon, Stephen B.; Fawcett, James W.

    2012-02-01

    Neural interfaces are implanted devices that couple the nervous system to electronic circuitry. They are intended for long term use to control assistive technologies such as muscle stimulators or prosthetics that compensate for loss of function due to injury. Here we present a novel design of interface for peripheral nerves. Recording from axons is complicated by the small size of extracellular potentials and the concentration of current flow at nodes of Ranvier. Confining axons to microchannels of ˜100 µm diameter produces amplified potentials that are independent of node position. After implantation of microchannel arrays into rat sciatic nerve, axons regenerated through the channels forming ‘mini-fascicles’, each typically containing ˜100 myelinated fibres and one or more blood vessels. Regenerated motor axons reconnected to distal muscles, as demonstrated by the recovery of an electromyogram and partial prevention of muscle atrophy. Efferent motor potentials and afferent signals evoked by muscle stretch or cutaneous stimulation were easily recorded from the mini-fascicles and were in the range of 35-170 µV. Individual motor units in distal musculature were activated from channels using stimulus currents in the microampere range. Microchannel interfaces are a potential solution for applications such as prosthetic limb control or enhancing recovery after nerve injury.

  5. Neuronal ADAM10 Promotes Outgrowth of Small-Caliber Myelinated Axons in the Peripheral Nervous System.

    PubMed

    Meyer zu Horste, Gerd; Derksen, Angelika; Stassart, Ruth; Szepanowski, Fabian; Thanos, Melissa; Stettner, Mark; Boettcher, Christina; Lehmann, Helmar C; Hartung, Hans-Peter; Kieseier, Bernd C

    2015-11-01

    The regulation of myelination and axonal outgrowth in the peripheral nervous system is controlled by a complex signaling network involving various signaling pathways. Members of the A Disintegrin And Metalloproteinase (ADAM) family are membrane-anchored proteinases with both proteolytic and disintegrin characteristics that modulate the function of signaling molecules. One family member, ADAM17, is known to influence myelination by cleaving and thus regulating one of the key signals, neuregulin-1, which controls peripheral nervous system myelination. A similar function for ADAM10 had been suggested by previous in vitro studies. Here, we assessed whether ADAM10 exerts a similar function in vivo and deleted ADAM10 in a cell type-specific manner in either neurons or Schwann cells. We found that ADAM10 is not required in either Schwann cells or neurons for normal myelination during development or for remyelination after injury. Instead, ADAM10 is required specifically in neurons for the outgrowth of myelinated small-fiber axons in vitro and after injury in vivo. Thus, we report for the first time a neuron-intrinsic function of ADAM10 in axonal regeneration that is distinct from that of the related protein family member ADAM17 and that may have implications for targeting ADAM function in nervous system diseases.

  6. Activation of axonal Kv7 channels in human peripheral nerve by flupirtine but not placebo - therapeutic potential for peripheral neuropathies: results of a randomised controlled trial

    PubMed Central

    2013-01-01

    Background Flupirtine is an analgesic with muscle-relaxing properties that activates Kv7 potassium channels. Kv7 channels are expressed along myelinated and unmyelinated peripheral axons where their activation is expected to reduce axonal excitability and potentially contribute to flupirtine’s clinical profile. Trial design To investigate the electrical excitability of peripheral myelinated axons following orally administered flupirtine, in-vitro experiments on isolated peripheral nerve segments were combined with a randomised, double-blind, placebo-controlled, phase I clinical trial (RCT). Methods Threshold tracking was used to assess the electrical excitability of myelinated axons in isolated segments of human sural nerve in vitro and motoneurones to abductor pollicis brevis (APB) in situ in healthy subjects. In addition, the effect of flupirtine on ectopic action potential generation in myelinated axons was examined using ischemia of the lower arm. Results Flupirtine (3-30 μM) shortened the relative refractory period and increased post-conditioned superexcitability in human myelinated axons in vitro. Similarly, in healthy subjects the relative refractory period of motoneurones to APB was reduced 2 hours after oral flupirtine but not following placebo. Whether this effect was due to a direct action of flupirtine on peripheral axons or temperature could not be resolved. Flupirtine (200 mg p.o.) also reduced ectopic axonal activity induced by 10 minutes of lower arm ischemia. In particular, high frequency (ca. 200 Hz) components of EMG were reduced in the post-ischemic period. Finally, visual analogue scale ratings of sensations perceived during the post-ischemic period were reduced following flupirtine (200 mg p.o.). Conclusions Clinical doses of flupirtine reduce the excitability of peripheral myelinated axons. Trial registration ClinicalTrials registration is NCT01450865. PMID:23394517

  7. A Systems-Level Analysis of the Peripheral Nerve Intrinsic Axonal Growth Program

    PubMed Central

    Chandran, Vijayendran; Coppola, Giovanni; Nawabi, Homaira; Omura, Takao; Versano, Revital; Huebner, Eric A.; Zhang, Alice; Costigan, Michael; Yekkirala, Ajay; Barrett, Lee; Blesch, Armin; Michaelevski, Izhak; Davis-Turak, Jeremy; Gao, Fuying; Langfelder, Peter; Horvath, Steve; He, Zhigang; Benowitz, Larry; Fainzilber, Mike; Tuszynski, Mark; Woolf, Clifford J.; Geschwind, Daniel H.

    2016-01-01

    SUMMARY The regenerative capacity of the injured CNS in adult mammals is severely limited, yet axons in the peripheral nervous system (PNS) regrow, albeit to a limited extent, after injury. We reasoned that coordinate regulation of gene expression in injured neurons involving multiple pathways was central to PNS regenerative capacity. To provide a framework for revealing pathways involved in PNS axon regrowth after injury, we applied a comprehensive systems biology approach, starting with gene expression profiling of dorsal root ganglia (DRGs) combined with multi-level bioinformatic analyses and experimental validation of network predictions. We used this rubric to identify a drug that accelerates DRG neurite outgrowth in vitro and optic nerve outgrowth in vivo by inducing elements of the identified network. The work provides a functional genomics foundation for understanding neural repair and proof of the power of such approaches in tackling complex problems in nervous system biology. PMID:26898779

  8. Sensory neuropathy in progressive motor neuronopathy (pmn) mice is associated with defects in microtubule polymerization and axonal transport.

    PubMed

    Schäfer, Michael K; Bellouze, Sarah; Jacquier, Arnaud; Schaller, Sébastien; Richard, Laurence; Mathis, Stéphane; Vallat, Jean-Michel; Haase, Georg

    2016-08-04

    Motor neuron diseases such as amyotrophic lateral sclerosis (ALS) are now recognized as multi-system disorders also involving various non-motor neuronal cell types. The precise extent and mechanistic basis of non-motor neuron damage in human ALS and ALS animal models remain however unclear. To address this, we here studied progressive motor neuronopathy (pmn) mice carrying a missense loss-of-function mutation in tubulin binding cofactor E (TBCE). These mice manifest a particularly aggressive form of motor axon dying back and display a microtubule loss, similar to that induced by human ALS-linked TUBA4A mutations. Using whole nerve confocal imaging of pmn × thy1.2-YFP16 fluorescent reporter mice and electron microscopy, we demonstrate axonal discontinuities, bead-like spheroids and ovoids in pmn suralis nerves indicating prominent sensory neuropathy. The axonal alterations qualitatively resemble those in phrenic motor nerves but do not culminate in the loss of myelinated fibers. We further show that the pmn mutation decreases the level of TBCE, impedes microtubule polymerization in dorsal root ganglion (DRG) neurons and causes progressive loss of microtubules in large and small caliber suralis axons. Live imaging of axonal transport using GFP-tagged tetanus toxin C-fragment (GFP-TTC) demonstrates defects in microtubule-based transport in pmn DRG neurons, providing a potential explanation for the axonal alterations in sensory nerves. This study unravels sensory neuropathy as a pathological feature of mouse pmn, and discusses the potential contribution of cytoskeletal defects to sensory neuropathy in human motor neuron disease.

  9. A diffusible signal attracts olfactory sensory axons toward their target in the developing brain of the moth.

    PubMed

    Oland, Lynne A; Pott, Wendy M; Howard, Charles T; Inlow, Mark; Buckingham, Jocelyn

    2003-07-01

    The signals that olfactory receptor axons use to navigate to their target in the CNS are still not well understood. In the moth Manduca sexta, the primary olfactory pathway develops postembryonically, and the receptor axons navigate from an experimentally accessible sensory epithelium to the brain along a pathway long enough for detailed study of regions in which axon behavior changes. The current experiments ask whether diffusible factors contribute to receptor axon guidance. Explants were made from the antennal receptor epithelium and co-cultured in a collagen gel matrix with slices of various regions of the brain. Receptor axons were attracted toward the central regions of the brain, including the protocerebrum and antennal lobe. Receptor axons growing into a slice of the most proximal region of the antennal nerve, where axon sorting normally occurs, showed no directional preference. When the antennal lobe was included in the slice, the receptor axons entering the sorting region grew directly toward the antennal lobe. Taken together with the previous in vivo experiments, the current results suggest that an attractive diffusible factor can serve as one cue to direct misrouted olfactory receptor axons toward the medial regions of the brain, where local cues guide them to the antennal lobe. They also suggest that under normal circumstances, in which the receptor axons follow a pre-existing pupal nerve to the antennal lobe, the diffusible factor emanating from the lobe acts in parallel and at short range to maintain the fidelity of the path into the antennal lobe. Copyright 2003 Wiley Periodicals, Inc. J Neurobiol 56: 24-40, 2003

  10. Reduced BACE1 activity enhances clearance of myelin debris and regeneration of axons in the injured peripheral nervous system

    PubMed Central

    Farah, Mohamed H.; Pan, Bao Han; Hoffman, Paul N.; Ferraris, Dana; Tsukamoto, Takashi; Nguyen, Thien; Wong, Philip C.; Price, Donald L.; Slusher, Barbara S.; Griffin, John W.

    2012-01-01

    β- site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is an aspartyl protease best known for its role in generating the amyloid β peptides that are present in plaques of Alzheimer's Disease. BACE1 has been an attractive target for drug development. In cultured embryonic neurons BACE1-cleaved N-terminal APP is further processed to generate a fragment that can trigger axonal degeneration, suggesting a vital role for BACE1 in axonal health. In addition, BACE1 cleaves neuregulin 1 type III, a protein critical for myelination of peripheral axons by Schwann cells during development. Here, we asked if axonal degeneration or axonal regeneration in adult nerves might be affected by inhibition or elimination of BACE1. We report that BACE1 knockout and wild-type nerves degenerated at a similar rate after axotomy and to a similar extent in the experimental neuropathies produced by administration of paclitaxel and acrylamide. These data indicate N-APP is not the sole culprit in axonal degeneration in adult nerves. Unexpectedly, however, we observed that BACE1 knockout mice had markedly enhanced clearance of axonal and myelin debris from degenerated fibers, accelerated axonal regeneration, and earlier reinnervation of neuromuscular junctions, compared to littermate controls. These observations were reproduced in part by pharmacological inhibition of BACE1. These data suggest BACE1 inhibition as a therapeutic approach to accelerate regeneration and recovery after peripheral nerve damage. PMID:21490216

  11. Anatomical basis of specific connections between sensory axons and motor neurons in the brachial spinal cord of the bullfrog.

    PubMed

    Lichtman, J W; Jhaveri, S; Frank, E

    1984-07-01

    The anatomical basis for the specificity of the monosynaptic stretch reflex has been studied in the brachial spinal cord of bullfrogs. Sensory axons from the triceps brachii muscle innervate the corresponding triceps motoneurons but do not innervate two types of unrelated motoneurons (subscapularis and pectoralis) (Lichtman, J.W., and E. Frank (1984) J. Neurosci. 4: 1745-1753). Retrograde labeling of these three types of motoneurons with horseradish peroxidase (HRP) demonstrated that their cell bodies had overlapping distributions in the lateral motor column, and their dendrites all occupied the same region of the dorsal horn. In addition, triceps sensory axons aborized extensively in the dorsal horn throughout the brachial spinal cord, with no obvious predilection for the region of the triceps motoneurons. Thus, the physiological specificity of these sensory-motor connections was not apparent from the anatomical location of the sensory or motor neurons. However, by injecting single pairs of related or unrelated sensory and motor cells with HRP, we found that related pairs formed anatomical contacts with each other more frequently than unrelated sensory-motor pairs did. These observations suggest that the specificity of these connections is most likely the result of local interactions between sensory and motor processes.

  12. Pharmacoethnicity in Paclitaxel-Induced Sensory Peripheral Neuropathy

    PubMed Central

    Komatsu, Masaaki; Wheeler, Heather E.; Chung, Suyoun; Low, Siew-Kee; Wing, Claudia; Delaney, Shannon M.; Gorsic, Lidija K.; Takahashi, Atsushi; Kubo, Michiaki; Kroetz, Deanna L.; Zhang, Wei; Nakamura, Yusuke; Dolan, M. Eileen

    2015-01-01

    Purpose Paclitaxel is used worldwide in the treatment of breast, lung, ovarian and other cancers. Sensory peripheral neuropathy is an associated adverse effect that cannot be predicted, prevented or mitigated. To better understand the contribution of germline genetic variation to paclitaxel-induced peripheral neuropathy, we undertook an integrative approach that combines genome-wide association study (GWAS) data generated from HapMap lymphoblastoid cell lines (LCLs) and Asian patients. Methods GWAS was performed with paclitaxel-induced cytotoxicity generated in 363 LCLs and with paclitaxel-induced neuropathy from 145 Asian patients. A gene-based approach was used to identify overlapping genes and compare to a European clinical cohort of paclitaxel-induced neuropathy. Neurons derived from human induced pluripotent stem cells were used for functional validation of candidate genes. Results SNPs near AIPL1 were significantly associated with paclitaxel-induced cytotoxicity in Asian LCLs (P < 10−6). Decreased expression of AIPL1 resulted in decreased sensitivity of neurons to paclitaxel by inducing neurite morphological changes as measured by increased relative total outgrowth, number of processes and mean process length. Using a gene-based analysis, there were 32 genes that overlapped between Asian LCL cytotoxicity and Asian patient neuropathy (P < 0.05) including BCR. Upon BCR knockdown, there was an increase in neuronal sensitivity to paclitaxel as measured by neurite morphological characteristics. Conclusion We identified genetic variants associated with Asian paclitaxel-induced cytotoxicity and functionally validated the AIPL1 and BCR in a neuronal cell model. Furthermore, the integrative pharmacogenomics approach of LCL/patient GWAS may help prioritize target genes associated with chemotherapeutic-induced peripheral neuropathy. PMID:26015512

  13. Pharmacoethnicity in Paclitaxel-Induced Sensory Peripheral Neuropathy.

    PubMed

    Komatsu, Masaaki; Wheeler, Heather E; Chung, Suyoun; Low, Siew-Kee; Wing, Claudia; Delaney, Shannon M; Gorsic, Lidija K; Takahashi, Atsushi; Kubo, Michiaki; Kroetz, Deanna L; Zhang, Wei; Nakamura, Yusuke; Dolan, M Eileen

    2015-10-01

    Paclitaxel is used worldwide in the treatment of breast, lung, ovarian, and other cancers. Sensory peripheral neuropathy is an associated adverse effect that cannot be predicted, prevented, or mitigated. To better understand the contribution of germline genetic variation to paclitaxel-induced peripheral neuropathy, we undertook an integrative approach that combines genome-wide association study (GWAS) data generated from HapMap lymphoblastoid cell lines (LCL) and Asian patients. GWAS was performed with paclitaxel-induced cytotoxicity generated in 363 LCLs and with paclitaxel-induced neuropathy from 145 Asian patients. A gene-based approach was used to identify overlapping genes and compare with a European clinical cohort of paclitaxel-induced neuropathy. Neurons derived from human-induced pluripotent stem cells were used for functional validation of candidate genes. SNPs near AIPL1 were significantly associated with paclitaxel-induced cytotoxicity in Asian LCLs (P < 10(-6)). Decreased expression of AIPL1 resulted in decreased sensitivity of neurons to paclitaxel by inducing neurite morphologic changes as measured by increased relative total outgrowth, number of processes and mean process length. Using a gene-based analysis, there were 32 genes that overlapped between Asian LCL cytotoxicity and Asian patient neuropathy (P < 0.05), including BCR. Upon BCR knockdown, there was an increase in neuronal sensitivity to paclitaxel as measured by neurite morphologic characteristics. We identified genetic variants associated with Asian paclitaxel-induced cytotoxicity and functionally validated the AIPL1 and BCR in a neuronal cell model. Furthermore, the integrative pharmacogenomics approach of LCL/patient GWAS may help prioritize target genes associated with chemotherapeutic-induced peripheral neuropathy. ©2015 American Association for Cancer Research.

  14. Treadmill Training Enhances Axon Regeneration In Injured Mouse Peripheral Nerves Without Increased Loss of Topographic Specificity

    PubMed Central

    English, Arthur W.; Cucoranu, Delia; Mulligan, Amanda; Sabatier, Manning

    2009-01-01

    We investigated the extent of misdirection of regenerating axons when that regeneration was enhanced using treadmill training. Retrograde fluorescent tracers were applied to the cut proximal stumps of the tibial and common fibular nerves two or four weeks after transection and surgical repair of the mouse sciatic nerve. The spatial locations of retrogradely labeled motoneurons were studied in untreated control mice and in mice receiving two weeks of treadmill training, either according to a continuous protocol (10 m/min, one hour/day, five day/week) or an interval protocol (20 m/min for two minutes, followed by a five minute rest, repeated 4 times, five days/week). More retrogradely labeled motoneurons were found in both treadmill trained groups. The magnitude of this increase was as great as or greater than that found after using other enhancement strategies. In both treadmill trained groups, the proportions of motoneurons labeled from tracer applied to the common fibular nerve that were found in spinal cord locations reserved for tibial motoneurons in intact mice was no greater than in untreated control mice and significantly less than found after electrical stimulation or chondroitinase treatment. Treadmill training in the first two weeks following peripheral nerve injury produces a marked enhancement of motor axon regeneration without increasing the propensity of those axons to choose pathways leading to functionally inappropriate targets. PMID:19731339

  15. Cerebellum tunes the excitability of the motor system: evidence from peripheral motor axons.

    PubMed

    Nodera, Hiroyuki; Manto, Mario

    2014-12-01

    Cerebellum is highly connected with the contralateral cerebral cortex. So far, the motor deficits observed in acute focal cerebellar lesions in human have been mainly explained on the basis of a disruption of the cerebello-thalamo-cortical projections. Cerebellar circuits have also numerous anatomical and functional interactions with brainstem nuclei and projects also directly to the spinal cord. Cerebellar lesions alter the excitability of peripheral motor axons as demonstrated by peripheral motor threshold-tracking techniques in cerebellar stroke. The biophysical changes are correlated with the functional scores. Nerve excitability measurements represent an attractive tool to extract the rules underlying the tuning of excitability of the motor pathways by the cerebellum and to discover the contributions of each cerebellar nucleus in this key function, contributing to early plasticity and sensorimotor learning.

  16. Benefit of chondroitinase ABC on sensory axon regeneration in a laceration model of spinal cord injury in the rat.

    PubMed

    Shields, Lisa B E; Zhang, Yi Ping; Burke, Darlene A; Gray, Rebecca; Shields, Christopher B

    2008-06-01

    Chondroitin sulfate proteoglycans are up-regulated in the spinal cord after SCI, creating a molecular barrier inhibitory to axon growth. Chondroitinase ABC degrades CSPGs in vitro and in vivo. We studied whether IT ChABC promotes axonal regeneration in a laceration model of SCI. Three groups of Sprague-Dawley rats were used: control and rats treated with low-dose and high-dose IT ChABC. Chondroitin sulfate proteoglycan breakdown products were measured by 2-B-6 expression, and intact CSPGs by CS-56 expression. Sensory axonal regeneration was traced after CTB injection into the median, ulnar, and sciatic nerves. CS-56 expression was down-regulated and 2-B-6 expression was increased in the groups treated with IT ChABC but not in the control. Laminin and GFAP immunoreactivity was unaltered in the ChABC groups. The number of axons growing into the scar was 3.1 times greater (P < .01) in the high-dose ChABC group and 2.1 times greater (P < .01) in the low-dose group compared with the controls. The length of axonal growth after high- and low-dose ChABC was 9.9 (P < .01) and 8.3 (P < .01) times greater, respectively, than in the control group. Axons extended across the lesion gap and into the distal spinal cord stump in 2 of 8 (low dose) and in 3 of 9 (high dose) rats compared with none in the control group. Intrathecal ChABC administration caused a slight decrease in CSPGs in the scar after a laceration SCI with a minimal increase in sensory axonal regeneration into and across the laceration gap.

  17. Benefit of Chondroitinase ABC on Sensory Axon Regeneration in a Laceration Model of Spinal Cord Injury in the Rat

    PubMed Central

    Shields, Lisa B. E.; Zhang, Yi Ping; Burke, Darlene A.; Gray, Rebecca; Shields, Christopher B.

    2008-01-01

    Background Chondroitin sulfate proteoglycans (CSPGs) are upregulated in the spinal cord following spinal cord injury (SCI) creating a molecular barrier inhibitory to axon growth. Chondroitinase ABC (ChABC) degrades CSPGs in vitro and in vivo. Methods We studied whether intrathecal (IT) ChABC promotes axonal regeneration in a laceration model of SCI. Three groups of Sprague Dawley rats were used: control and rats treated with low dose and high dose IT ChABC. CSPG breakdown products were measured by 2-B-6 expression, and intact CSPGs by CS-56 expression. Sensory axonal regeneration was traced following CTB injection into the median, ulnar, and sciatic nerves. Results CS-56 expression was downregulated and 2-B-6 expression was increased in the groups treated with IT ChABC but not in the control. Laminin and GFAP immunoreactivity was unaltered in the ChABC groups. The number of axons growing into the scar was 3.1 times greater (p<0.01) in the high dose ChABC group and 2.1 times greater (p<0.01) in the low dose group compared to the controls. The length of axonal growth following high and low dose ChABC was 9.9 (p<0.01) and 8.3 (p<0.01) times greater, respectively, than in the control group. Axons extended across the lesion gap and into the distal spinal cord stump in 2/8 (low dose) and in 3/9 (high dose) rats compared to none in the control group. Conclusions IT ChABC administration caused a slight decrease in CSPGs in the scar following a laceration SCI with a minimal increase in sensory axonal regeneration into and across the laceration gap. PMID:18486695

  18. Retrograde axonal transport of ciliary neurotrophic factor is increased by peripheral nerve injury.

    PubMed

    Curtis, R; Adryan, K M; Zhu, Y; Harkness, P J; Lindsay, R M; DiStefano, P S

    1993-09-16

    Ciliary neurotrophic factor (CNTF) promotes the survival of several populations of neurons, including sensory and motor neurons. Although CNTF is abundant in adult sciatic nerve, the mature protein lacks a signal sequence and is not secreted; therefore, it has been proposed to act as a lesion factor. The identification of a functional CNTF receptor revealed ligand-specific phosphorylation cascades and gene induction. However, it is not clear how these signal-transducing events are elicited in neuronal cell bodies that may be distant from the source of CNTF. We report here that CNTF can be retrogradely transported by adult sensory neurons. More importantly, sensory and motor neurons both show greatly increased transport of CNTF following peripheral nerve lesion. Axotomy-induced increases in retrograde transport of neurotrophic factors may be an important response of neuronal cell bodies during regeneration.

  19. Cxcl12/Cxcr4 chemokine signaling is required for placode assembly and sensory axon pathfinding in the zebrafish olfactory system.

    PubMed

    Miyasaka, Nobuhiko; Knaut, Holger; Yoshihara, Yoshihiro

    2007-07-01

    Positioning neurons in the right places and wiring axons to the appropriate targets are essential events for establishment of neural circuits. In the zebrafish olfactory system, precursors of olfactory sensory neurons (OSNs) assemble into a compact cluster to form the olfactory placode. Subsequently, OSNs differentiate and extend their axons to the presumptive olfactory bulb with high precision. In this study, we aim to elucidate the molecular mechanism underlying these two developmental processes. cxcr4b, encoding a chemokine receptor, is expressed in the migrating olfactory placodal precursors, and cxcl12a (SDF-1a), encoding a ligand for Cxcr4b, is expressed in the abutting anterior neural plate. The expression of cxcr4b persists in the olfactory placode at the initial phase of OSN axon pathfinding. At this time, cxcl12a is expressed along the placode-telencephalon border and at the anterior tip of the telencephalon, prefiguring the route and target of OSN axons, respectively. Interfering with Cxcl12a/Cxcr4b signaling perturbs the assembly of the olfactory placode, resulting in the appearance of ventrally displaced olfactory neurons. Moreover, OSN axons frequently fail to exit the olfactory placode and accumulate near the placode-telencephalon border in the absence of Cxcr4b-mediated signaling. These data indicate that chemokine signaling contributes to both the olfactory placode assembly and the OSN axon pathfinding in zebrafish.

  20. Kirrel3 is required for the coalescence of vomeronasal sensory neuron axons into glomeruli and for male-male aggression

    PubMed Central

    Prince, Janet E. A.; Brignall, Alexandra C.; Cutforth, Tyler; Shen, Kang; Cloutier, Jean-François

    2013-01-01

    The accessory olfactory system controls social and sexual interactions in mice that are crucial for survival. Vomeronasal sensory neurons (VSNs) form synapses with dendrites of second order neurons in glomeruli of the accessory olfactory bulb (AOB). Axons of VSNs expressing the same vomeronasal receptor coalesce into multiple glomeruli within spatially conserved regions of the AOB. Here we examine the role of the Kirrel family of transmembrane proteins in the coalescence of VSN axons within the AOB. We find that Kirrel2 and Kirrel3 are differentially expressed in subpopulations of VSNs and that their expression is regulated by activity. Although Kirrel3 expression is not required for early axonal guidance events, such as fasciculation of the vomeronasal tract and segregation of apical and basal VSN axons in the AOB, it is necessary for proper coalescence of axons into glomeruli. Ablation of Kirrel3 expression results in disorganization of the glomerular layer of the posterior AOB and formation of fewer, larger glomeruli. Furthermore, Kirrel3−/− mice display a loss of male-male aggression in a resident-intruder assay. Taken together, our results indicate that differential expression of Kirrels on vomeronasal axons generates a molecular code that dictates their proper coalescence into glomeruli within the AOB. PMID:23637329

  1. NADPH-diaphorase histochemistry selectively stains peripheral and central sensory structures of lumbricid earhworms.

    PubMed

    Solt, Zsuzsanna; Zsombok, Andrea; Pollák, Edit; Molnár, László

    2016-12-01

    By means of whole mount NADPH-diaphorase histochemistry the distribution pattern of primary sensory cells (PSC) and the pathway of their central processes in the ventral nerve cord (VNC) ganglia were investigated in the lumbricid earthworms, Eisenia fetida and Lumbricus terrestris. The distribution pattern of the stained structures seemed to be the same in both species investigated. Strong labelling occurred in sensory fibre branches of segmental nerves and in each of the sensory longitudinal axon bundles of VNC ganglia. Based on their anatomical location some NADPH-d positive central sensory cells were identified from among which the putative tactile receptors were characterized by constant, strong staining.

  2. An RNA Binding Protein Promotes Axonal Integrity in Peripheral Neurons by Destabilizing REST

    PubMed Central

    Cargnin, Francesca; Nechiporuk, Tamilla; Müllendorff, Karin; Stumpo, Deborah J.; Blackshear, Perry J.; Ballas, Nurit

    2014-01-01

    The RE1 Silencing Transcription Factor (REST) acts as a governor of the mature neuronal phenotype by repressing a large consortium of neuronal genes in non-neuronal cells. In the developing nervous system, REST is present in progenitors and downregulated at terminal differentiation to promote acquisition of mature neuronal phenotypes. Paradoxically, REST is still detected in some regions of the adult nervous system, but how REST levels are regulated, and whether REST can still repress neuronal genes, is not known. Here, we report that homeostatic levels of REST are maintained in mature peripheral neurons by a constitutive post-transcriptional mechanism. Specifically, using a three-hybrid genetic screen, we identify the RNA binding protein, ZFP36L2, associated previously only with female fertility and hematopoiesis, and show that it regulates REST mRNA stability. Dorsal root ganglia in Zfp36l2 knock-out mice, or wild-type ganglia expressing ZFP36L2 shRNA, show higher steady-state levels of Rest mRNA and protein, and extend thin and disintegrating axons. This phenotype is due, at least in part, to abnormally elevated REST levels in the ganglia because the axonal phenotype is attenuated by acute knockdown of REST in Zfp36l2 KO DRG explants. The higher REST levels result in lower levels of target genes, indicating that REST can still fine-tune gene expression through repression. Thus, REST levels are titrated in mature peripheral neurons, in part through a ZFP36L2-mediated post-transcriptional mechanism, with consequences for axonal integrity. PMID:25505318

  3. 4-Hydroxy-2-nonenal induces mitochondrial dysfunction and aberrant axonal outgrowth in adult sensory neurons that mimics features of diabetic neuropathy.

    PubMed

    Akude, Eli; Zherebitskaya, Elena; Roy Chowdhury, Subir K; Girling, Kimberly; Fernyhough, Paul

    2010-01-01

    Modification of proteins by 4-hydroxy-2-nonenal (4-HNE) has been proposed to cause neurotoxicity in a number of neurodegenerative diseases, including distal axonopathy in diabetic sensory neuropathy. We tested the hypothesis that exposure of cultured adult rat sensory neurons to 4-HNE would result in the formation of amino acid adducts on mitochondrial proteins and that this process would be associated with impaired mitochondrial function and axonal regeneration. In addition, we compared 4-HNE-induced axon pathology with that exhibited by neurons isolated from diabetic rats. Cultured adult rat dorsal root ganglion (DRG) sensory neurons were incubated with varying concentrations of 4-HNE. Cell survival, axonal morphology, and level of axon outgrowth were assessed. In addition, video microscopy of live cells, western blot, and immunofluorescent staining were utilized to detect protein adduct formation by 4-HNE and to localize actively respiring mitochondria. 4-HNE induced formation of protein adducts on cytoskeletal and mitochondrial proteins, and impaired axon regeneration by approximately 50% at 3 microM while having no effect on neuronal survival. 4-HNE initiated formation of aberrant axonal structures and caused the accumulation of mitochondria in these dystrophic structures. Neurons treated with 4-HNE exhibited a distal loss of active mitochondria. Finally, the distal axonopathy and the associated aberrant axonal structures generated by 4-HNE treatment mimicked axon pathology observed in DRG sensory neurons isolated from diabetic rats and replicated aspects of neurodegeneration observed in human diabetic sensory neuropathy.

  4. Role of sensory-motor cortex activity in postnatal development of corticospinal axon terminals in the cat.

    PubMed

    Friel, Kathleen M; Martin, John H

    2005-04-25

    The initial pattern of corticospinal (CS) terminations, as axons grow into the spinal gray matter, bears little resemblance to the pattern later in development and in maturity. This is because of extensive axon pruning and local axon terminal growth during early postnatal development. Pruning is driven by activity-dependent competition between the CS systems on each side during postnatal weeks (PW) 3-7. It is not known whether CS axon terminal growth and final topography are activity dependent. We examined the activity dependence of CS axon terminal growth and topography at different postnatal times. We inactivated sensory-motor cortex by infusion of the gamma-aminobutyric acid type A (GABA(A)) agonist muscimol and traced CS axons from the inactivated side. Inactivation between PW5 and PW7 produced permanent changes in projection topography, reduced local axon branching, and prevented development of dense clusters of presynaptic sites, which are normally characteristic of CS terminals. Inactivation at younger (PW3-5) and older (PW8-12) ages did not affect projection topography but impeded development of local axon branching and presynaptic site clusters. These effects were not due to increased cortical cell death during inactivation. Neural activity plays an important role in determining the morphology of CS terminals during the entire period of development, but, for the projection topography, the role of activity is exercised during a very brief period. This points to a complex, and possibly independent, regulation of termination topography and terminal morphology. Surprisingly, when a CS neuron's activity is blocked during early development, it does not recover lost connections later in development once activity resumes.

  5. Peripheral Sensory Neuropathy Associates With Micro- or Macroangiopathy

    PubMed Central

    Kärvestedt, Lars; Mårtensson, Eva; Grill, Valdemar; Elofsson, Stig; von Wendt, Gunvor; Hamsten, Anders; Brismar, Kerstin

    2009-01-01

    OBJECTIVE—To assess associations between peripheral sensory neuropathy (PSN) and other diabetes-related complications. RESEARCH DESIGN AND METHOD—In an area-based cohort of type 2 diabetic subjects, we investigated 156 subjects (age 61.7 ± 7.2 years and diabetes duration 7.0 ± 5.7 years) by questionnaires, clinical examinations, blood and urine sampling, and review of medical records. RESULTS—Prevalence of PSN, assessed by monofilament and neurothesiometer testing, increased with severity of retinopathy (50% frequency in moderate and 100% in severe or proliferative retinopathy; P = 0.02). Vibration perception threshold was higher in subjects with retinopathy (25.6 ± 8.9 vs. 20.5 ± 8.9 V; P = 0.007). PSN was more common in subjects with overt nephropathy, with higher vibration perception thresholds, than in subjects without overt nephropathy. Subjects with PSN but no retinopathy had twice the prevalence of peripheral vascular disease (PVD) (52%) as subjects with both PSN and retinopathy (19%; P = 0.05). In subjects with PSN alone, PVD was three times more likely (52%) than in subjects without PSN (16%; P = 0.001). In multivariate analysis, PSN was independently associated with PVD (odds ratio 2.31; P = 0.007), age (1.12; P = 0.008), male sex (2.01; P = 0.02), and HDL cholesterol (0.21; P < 0.05) and tended to be independently associated with IGF-1 binding protein (1.03; P = 0.05) but not with diabetes duration or A1C. CONCLUSIONS—In a representative population of type 2 diabetes, PSN is related to microvascular and macrovascular pathology. PSN is possibly affected by the IGF axis. PMID:19033412

  6. Immune response in peripheral axons delays disease progression in SOD1(G93A) mice.

    PubMed

    Nardo, Giovanni; Trolese, Maria Chiara; de Vito, Giuseppe; Cecchi, Roberta; Riva, Nilo; Dina, Giorgia; Heath, Paul R; Quattrini, Angelo; Shaw, Pamela J; Piazza, Vincenzo; Bendotti, Caterina

    2016-10-07

    Increasing evidence suggests that the immune system has a beneficial role in the progression of amyotrophic lateral sclerosis (ALS) although the mechanism remains unclear. Recently, we demonstrated that motor neurons (MNs) of C57SOD1(G93A) mice with slow disease progression activate molecules classically involved in the cross-talk with the immune system. This happens a lot less in 129SvSOD1(G93A) mice which, while expressing the same amount of transgene, had faster disease progression and earlier axonal damage. The present study investigated whether and how the immune response is involved in the preservation of motor axons in the mouse model of familial ALS with a more benign disease course. First, the extent of axonal damage, Schwann cell proliferation, and neuromuscular junction (NMJ) denervation were compared between the two ALS mouse models at the disease onset. Then, we compared the expression levels of different immune molecules, the morphology of myelin sheaths, and the presence of blood-derived immune cell infiltrates in the sciatic nerve of the two SOD1G93A mouse strains using immunohistochemical, immunoblot, quantitative reverse transcription PCR, and rotating-polarization Coherent Anti-Stokes Raman Scattering techniques. Muscle denervation, axonal dysregulation, and myelin disruption together with reduced Schwann cell proliferation are prominent in 129SvSOD1(G93A) compared to C57SOD1(G93A) mice at the disease onset, and this correlates with a faster disease progression in the first strain. On the contrary, a striking increase of immune molecules such as CCL2, MHCI, and C3 was seen in sciatic nerves of slow progressor C57SOD1(G93A) mice and this was accompanied by heavy infiltration of CD8(+) T lymphocytes and macrophages. These phenomena were not detectable in the peripheral nervous system of fast-progressing mice. These data show for the first time that damaged MNs in SOD1-related ALS actively recruit immune cells in the peripheral nervous system to

  7. [A case of sensory ataxic axonal polyneuropathy with IgGλ monoclonal gammopathy successfully treated with intravenous immunoglobulin therapy].

    PubMed

    Kanatsuka, Yoichi; Hasegawa, Osamu; Imazeki, Ryoko; Yamamoto, Masahiro

    2015-01-01

    We report the case of an 84-year-old man with sensory ataxic polyneuropathy and IgGλ monoclonal gammopathy of undetermined significance (MGUS), which was successfully treated with intravenous immunoglobulin (IVIG) therapy. He had developed progressive ataxic gait over the span of 2 years before he was admitted to our hospital. On admission, he was unable to walk without assistance because of severe sensory ataxia. He performed poorly on the finger-nose-finger and heel-knee tests, and his vibration and position sense in the feet was remarkably diminished. However, motor involvement was not remarkable. Serum immunoelectrophoresis revealed IgGλ monoclonal gammopathy, and MGUS was diagnosed. Nerve conduction studies revealed sensory-dominant axonal polyneuropathy. The patient was successfully treated with IVIG (400 mg/kg/day, for 5 days). He regained his capacity to walk independently after treatment, but his nerve conduction results remained unchanged. This sensory ataxia might be partially due to underlying cervical spondylotic myelopathy. To our knowledge, this is the first report in our country of the successful use of IVIG therapy to treat a patient with IgGλ monoclonal gammopathy and related sensory ataxic axonal polyneuropathy.

  8. Peripheral Sensory Neurons Expressing Melanopsin Respond to Light

    PubMed Central

    Matynia, Anna; Nguyen, Eileen; Sun, Xiaoping; Blixt, Frank W.; Parikh, Sachin; Kessler, Jason; Pérez de Sevilla Müller, Luis; Habib, Samer; Kim, Paul; Wang, Zhe Z.; Rodriguez, Allen; Charles, Andrew; Nusinowitz, Steven; Edvinsson, Lars; Barnes, Steven; Brecha, Nicholas C.; Gorin, Michael B.

    2016-01-01

    The ability of light to cause pain is paradoxical. The retina detects light but is devoid of nociceptors while the trigeminal sensory ganglia (TG) contain nociceptors but not photoreceptors. Melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) are thought to mediate light-induced pain but recent evidence raises the possibility of an alternative light responsive pathway independent of the retina and optic nerve. Here, we show that melanopsin is expressed in both human and mouse TG neurons. In mice, they represent 3% of small TG neurons that are preferentially localized in the ophthalmic branch of the trigeminal nerve and are likely nociceptive C fibers and high-threshold mechanoreceptor Aδ fibers based on a strong size-function association. These isolated neurons respond to blue light stimuli with a delayed onset and sustained firing, similar to the melanopsin-dependent intrinsic photosensitivity observed in ipRGCs. Mice with severe bilateral optic nerve crush exhibit no light-induced responses including behavioral light aversion until treated with nitroglycerin, an inducer of migraine in people and migraine-like symptoms in mice. With nitroglycerin, these same mice with optic nerve crush exhibit significant light aversion. Furthermore, this retained light aversion remains dependent on melanopsin-expressing neurons. Our results demonstrate a novel light-responsive neural function independent of the optic nerve that may originate in the peripheral nervous system to provide the first direct mechanism for an alternative light detection pathway that influences motivated behavior. PMID:27559310

  9. Axonal degeneration in peripheral nerves in a case of Leber hereditary optic neuropathy.

    PubMed

    Mnatsakanyan, Lilit; Ross-Cisneros, Fred N; Carelli, Valerio; Wang, Michelle Y; Sadun, Alfredo A

    2011-03-01

    Leber hereditary optic neuropathy (LHON) is a mitochondrial DNA (mtDNA) genetic disorder characterized by profound bilateral loss of central vision due to selective loss of retinal ganglion cells. Most patients with LHON do not have complaints related to the peripheral nervous system. We investigated possible qualitative and quantitative histological changes in the peripheral nerve of a patient with LHON as compared to normal controls. Brachial plexus specimens were obtained at necropsy from a patient with LHON carrying the 3460/ND1 mtDNA mutation and age-matched controls without known history of neurological disease. The nerves were evaluated by light microscope coupled to a digital camera-based morphometric analysis and electron microscopy. Extensive axonal degeneration of the large heavily myelinated fibers was found in the brachial plexus from the patient with LHON. In LHON nerve fascicles, we counted over 10 times as many degenerated profiles as found in the control nerve fascicles. Microscopic examination of the brachial plexus in the patient with LHON clearly demonstrated a significant pattern of neurodegeneration. Our study suggests that peripheral neuropathy may be a subclinical feature associated with LHON.

  10. Electrical stimulation combined with exercise increase axonal regeneration after peripheral nerve injury.

    PubMed

    Asensio-Pinilla, Elena; Udina, Esther; Jaramillo, Jessica; Navarro, Xavier

    2009-09-01

    Although injured peripheral axons are able to regenerate, functional recovery is usually poor after nerve transection. In this study we aim to elucidate the role of neuronal activity, induced by nerve electrical stimulation and by exercise, in promoting axonal regeneration and modulating plasticity in the spinal cord after nerve injury. Four groups of adult rats were subjected to sciatic nerve transection and suture repair. Two groups received electrical stimulation (3 V, 0.1 ms at 20 Hz) for 1 h, immediately after injury (ESa) or during 4 weeks (1 h daily; ESc). A third group (ES+TR) received 1 h electrical stimulation and was submitted to treadmill running during 4 weeks (5 m/min, 2 h daily). A fourth group performed only exercise (TR), whereas an untreated group served as control (C). Nerve conduction, H reflex and algesimetry tests were performed at 1, 3, 5, 7 and 9 weeks after surgery, to assess muscle reinnervation and changes in excitability of spinal cord circuitry. Histological analysis was made at the end of the follow-up. Groups that received acute ES and/or were forced to exercise in the treadmill showed higher levels of muscle reinnervation and increased numbers of regenerated myelinated axons when compared to control animals or animals that received chronic ES. Combining ESa with treadmill training significantly improved muscle reinnervation during the initial phase. The facilitation of the monosynaptic H reflex in the injured limb was reduced in all treated groups, suggesting that the maintenance of activity helps to prevent the development of hyperreflexia.

  11. Stress Increases Peripheral Axon Growth and Regeneration through Glucocorticoid Receptor-Dependent Transcriptional Programs

    PubMed Central

    Alexander, Jessica K.; Madalena, Kathryn M.; Motti, Dario; Quach, Tam; Zha, Alicia; Webster Marketon, Jeanette

    2017-01-01

    Abstract Stress and glucocorticoid (GC) release are common behavioral and hormonal responses to injury or disease. In the brain, stress/GCs can alter neuron structure and function leading to cognitive impairment. Stress and GCs also exacerbate pain, but whether a corresponding change occurs in structural plasticity of sensory neurons is unknown. Here, we show that in female mice (Mus musculus) basal GC receptor (Nr3c1, also known as GR) expression in dorsal root ganglion (DRG) sensory neurons is 15-fold higher than in neurons in canonical stress-responsive brain regions (M. musculus). In response to stress or GCs, adult DRG neurite growth increases through mechanisms involving GR-dependent gene transcription. In vivo, prior exposure to an acute systemic stress increases peripheral nerve regeneration. These data have broad clinical implications and highlight the importance of stress and GCs as novel behavioral and circulating modifiers of neuronal plasticity. PMID:28828403

  12. Stress Increases Peripheral Axon Growth and Regeneration through Glucocorticoid Receptor-Dependent Transcriptional Programs.

    PubMed

    Lerch, Jessica K; Alexander, Jessica K; Madalena, Kathryn M; Motti, Dario; Quach, Tam; Dhamija, Akhil; Zha, Alicia; Gensel, John C; Webster Marketon, Jeanette; Lemmon, Vance P; Bixby, John L; Popovich, Phillip G

    2017-01-01

    Stress and glucocorticoid (GC) release are common behavioral and hormonal responses to injury or disease. In the brain, stress/GCs can alter neuron structure and function leading to cognitive impairment. Stress and GCs also exacerbate pain, but whether a corresponding change occurs in structural plasticity of sensory neurons is unknown. Here, we show that in female mice (Mus musculus) basal GC receptor (Nr3c1, also known as GR) expression in dorsal root ganglion (DRG) sensory neurons is 15-fold higher than in neurons in canonical stress-responsive brain regions (M. musculus). In response to stress or GCs, adult DRG neurite growth increases through mechanisms involving GR-dependent gene transcription. In vivo, prior exposure to an acute systemic stress increases peripheral nerve regeneration. These data have broad clinical implications and highlight the importance of stress and GCs as novel behavioral and circulating modifiers of neuronal plasticity.

  13. Sustained Growth Factor Delivery Promotes Axonal Regeneration in Long Gap Peripheral Nerve Repair

    PubMed Central

    Kokai, Lauren E.; Bourbeau, Dennis; Weber, Douglas; McAtee, Jedidiah

    2011-01-01

    The aim of this study was to evaluate the long-term effect of localized growth factor delivery on sciatic nerve regeneration in a critical-size (>1 cm) peripheral nerve defect. Previous work has demonstrated that bioactive proteins can be encapsulated within double-walled, poly(lactic-co-glycolic acid)/poly(lactide) microspheres and embedded within walls of biodegradable polymer nerve guides composed of poly(caprolactone). Within this study, nerve guides containing glial cell line-derived neurotrophic factor (GDNF) were used to bridge a 1.5-cm defect in the male Lewis rat for a 16-week period. Nerve repair was evaluated through functional assessment of joint angle range of motion using video gait kinematics, gastrocnemius twitch force, and gastrocnemius wet weight. Histological evaluation of nerve repair included assessment of Schwann cell and neurofilament location with immunohistochemistry, evaluation of tissue integration and organization throughout the lumen of the regenerated nerve with Masson's trichrome stain, and quantification of axon fiber density and g-ratio. Results from this study showed that the measured gastrocnemius twitch force in animals treated with GDNF was significantly higher than negative controls and was not significantly different from the isograft-positive control group. Histological assessment of explanted conduits after 16 weeks showed improved tissue integration within GDNF releasing nerve guides compared to negative controls. Nerve fibers were present across the entire length of GDNF releasing guides, whereas nerve fibers were not detectable beyond the middle region of negative control guides. Therefore, our results support the use of GDNF for improved functional recovery above negative controls following large axonal defects in the peripheral nervous system. PMID:21189072

  14. Towing of sensory axons by their migrating target cells in vivo.

    PubMed

    Gilmour, Darren; Knaut, Holger; Maischein, Hans-Martin; Nüsslein-Volhard, Christiane

    2004-05-01

    Many pathfinding axons must locate target fields that are themselves positioned by active migration. A hypothetical method for ensuring that these migrations are coordinated is towing, whereby the extension of axons is entirely dependent on the migration of their target cells. Here we combine genetics and time-lapse imaging in the zebrafish to show that towing by migrating cells is a bona fide mechanism for guiding pathfinding axons in vivo.

  15. The cell bodies of origin of sympathetic and sensory axons in some skin and muscle nerves of the cat hindlimb.

    PubMed

    McLachlan, E M; Jänig, W

    1983-02-20

    Cell bodies of sensory and sympathetic axons projecting to skin and skeletal muscle of the cat hindlimb have been labeled retrogradely with horseradish peroxidase (HRP) in order to study location, size, and numbers of the somata of these neurons. HRP was applied to the freshly transected axons of nerves supplying hairy skin (superficial peroneal, SP; sural, Su), hairy and hairless skin of the paw (medial plantar, MP), or skeletal muscle (gastrocnemius-soleus, GS). Serial sections of lumbosacral dorsal root and sympathetic ganglia were studied after standard histochemical processing. Additionally, the numbers of myelinated fibers in the same nerves were determined. All sensory somata and 99.4% of sympathetic cell bodies were located ipsilaterally. Sensory somata were commonly restricted to two adjacent dorsal root ganglia (usually L6-7 for SP, MP; L7-S1 for Su, GS). Although sympathetic somata were more widely distributed rostrocaudally, their maximum frequency always occurred in the segmental ganglia immediately rostral to the sensory outflows, i.e., corresponding to rami communicantes grisei. Dimensions of sympathetic somata varied little between populations projecting to different tissues and were unimodally distributed. The size distributions of sensory somata were characterized by a peak between 10 and 20 microns radius, similar to sympathetic somata, and a varying smaller number of cells ranging up to 60 microns radius. Each nerve had a characteristic distribution profile of afferent somata. A population of very small cells was only present in GS, while the largest sensory somata in GS and MP were bigger than those in SP and Su. Numerical analysis of the data disclosed the characteristic composition of both myelinated and unmyelinated fibers in each nerve studied.

  16. Robo-2 controls the segregation of a portion of basal vomeronasal sensory neuron axons to the posterior region of the accessory olfactory bulb.

    PubMed

    Prince, Janet E A; Cho, Jin Hyung; Dumontier, Emilie; Andrews, William; Cutforth, Tyler; Tessier-Lavigne, Marc; Parnavelas, John; Cloutier, Jean-François

    2009-11-11

    The ability of sensory systems to detect and process information from the environment relies on the elaboration of precise connections between sensory neurons in the periphery and second order neurons in the CNS. In mice, the accessory olfactory system is thought to regulate a wide variety of social and sexual behaviors. The expression of the Slit receptors Robo-1 and Robo-2 in vomeronasal sensory neurons (VSNs) suggests they may direct the stereotypic targeting of their axons to the accessory olfactory bulb (AOB). Here, we have examined the roles of Robo-1 and Robo-2 in the formation of connections by VSN axons within the AOB. While Robo-1 is not necessary for the segregation of VSN axons within the anterior and posterior regions of the AOB, Robo-2 is required for the targeting of some basal VSN axons to the posterior region of the AOB but is dispensable for the fasciculation of VSN axons. Furthermore, the specific ablation of Robo-2 expression in VSNs leads to mistargeting of a portion of basal VSN axons to the anterior region of the AOB, indicating that Robo-2 expression is required on projecting VSN axons. Together, these results identify Robo-2 as a receptor that controls the targeting of basal VSN axons to the posterior AOB.

  17. TRPV2 enhances axon outgrowth through its activation by membrane stretch in developing sensory and motor neurons.

    PubMed

    Shibasaki, Koji; Murayama, Namie; Ono, Katsuhiko; Ishizaki, Yasuki; Tominaga, Makoto

    2010-03-31

    Thermosensitive TRP (thermo TRP) channels are well recognized for their contributions to sensory transduction, responding to a wide variety of stimuli including temperature, nociceptive stimuli, touch, and osmolarity. However, the precise roles for the thermo TRP channels during development have not been determined. To explore the functional importance of thermo TRP channels during neural development, the temporal expression was determined in embryonic mice. Interestingly, TRPV2 expression was detected in spinal motor neurons in addition to the dorsal root ganglia from embryonic day 10.5 and was localized in axon shafts and growth cones, suggesting that the channel is important for axon outgrowth regulation. We revealed that endogenous TRPV2 was activated in a membrane stretch-dependent manner in developing neurons by knocking down the TRPV2 function with dominant-negative TRPV2 and TRPV2-specific shRNA and significantly promoted axon outgrowth. Thus, for the first time we revealed that TRPV2 is an important regulator for axon outgrowth through its activation by membrane stretch during development.

  18. Peripheral Sensory Neuropathy and associated factors among adult diabetes mellitus patients in Bahr Dar, Ethiopia.

    PubMed

    Jember, Gashaw; Melsew, Yayehirad Alemu; Fisseha, Berihu; Sany, Kedir; Gelaw, Asmare Yitayeh; Janakiraman, Balamurugan

    2017-01-01

    Diabetic sensory neuropathy is a common form of microvascular complication among diabetic patients. The swiftly growing population of people living with diabetes in Ethiopia and lack of elaborated scientific data on peripheral sensory neuropathy among diabetic population in Ethiopia prompted this work. This study was set out to assess the enormity and associated factors of peripheral sensory neuropathy among diabetes patients attending chronic illness clinic of Felege Hiwot Regional Referral Hospital, Bahr Dar, Northwest Ethiopia. An institution based cross-sectional study was conducted at Felege Hiwot Referral Hospital chronic illness clinic using Michigan neuropathy screening instrument tool for diabetic peripheral sensory neuropathy on 408 diabetic patients during 2016. Data were collected using interview, patient record review, anthropometric measurements and physical examination. Both bivariate and multivariate binary logistic regression was employed to identify factors associated with peripheral sensory neuropathy. Odds ratios with their 95% CI and P value less than 0.05 used to determine statistically significant associations. A total of 368 patients were included with the mean age of 49 ± 14.3 years. The overall prevalence of Peripheral Sensory Neuropathy was found to be 52.2%. The major associated factors identified by multivariate analysis were age >50 years: AOR: 3.0 CI [1.11, 7.89]; overweight and obese: AOR: 7.3 CI [3.57, 14.99]; duration of DM: AOR: 3.4 CI [1.75, 6.60]; not involved in physical exercise: AOR: 4.8 CI [1.90, 7.89]; male gender: AOR: 2.4 CI [1.18, 5.05]. Almost half of the diabetic patients who attended Felege Hiwot regional referral hospital during study period were found to present with peripheral sensory neuropathy. Socio-demographic and bio characteristics like patients age, Body Mass Index, level of physical activity and marital status were significantly associated with diabetic peripheral sensory neuropathy.

  19. Neurotrophin-4/5 is implicated in the enhancement of axon regeneration produced by treadmill training following peripheral nerve injury

    PubMed Central

    English, Arthur W.; Cucoranu, Delia; Mulligan, Amanda; Rodriguez, José A.; Sabatier, Manning J.

    2011-01-01

    The role of neurotrophin-4/5 in the enhancement of axon regeneration in peripheral nerves produced by treadmill training was studied in mice. Common fibular nerves of animals of the H strain of thy-1-YFP mice, in which a subset of axons in peripheral nerves is marked by the presence of yellow fluorescent protein, were cut and surgically repaired using nerve grafts from non-fluorescent mice. Lengths of profiles of fluorescent regenerating axons were measured using optical sections made through whole mounts of harvested nerves. Measurements from mice that had undergone one hour of daily treadmill training at modest speed (10 m/min) were compared to those of untrained (control) mice. Modest treadmill training resulted in fluorescent axon profiles that were nearly twice as long as controls at one, two and four week survival times. Similar enhanced regeneration was found when cut nerves of wild type mice were repaired with grafts from neurotrophin-4/5 knockout mice or grafts made acellular by repeated freezing/thawing. No enhancement was produced by treadmill training in neurotrophin-4/5 knockout mice, irrespective of the nature of the graft used to repair the cut nerve. Much as had been observed previously for the effects of brief electrical stimulation, the effects of treadmill training on axon regeneration in cut peripheral nerves are independent of changes produced in the distal segment of the cut nerve and depend on the promotion of axon regeneration by changes in NT-4/5 expression by cells in the proximal nerve segment. PMID:21623957

  20. N- and L-Type Voltage-Gated Calcium Channels Mediate Fast Calcium Transients in Axonal Shafts of Mouse Peripheral Nerve

    PubMed Central

    Barzan, Ruxandra; Pfeiffer, Friederike; Kukley, Maria

    2016-01-01

    In the peripheral nervous system (PNS) a vast number of axons are accommodated within fiber bundles that constitute peripheral nerves. A major function of peripheral axons is to propagate action potentials along their length, and hence they are equipped with Na+ and K+ channels, which ensure successful generation, conduction and termination of each action potential. However little is known about Ca2+ ion channels expressed along peripheral axons and their possible functional significance. The goal of the present study was to test whether voltage-gated Ca2+ channels (VGCCs) are present along peripheral nerve axons in situ and mediate rapid activity-dependent Ca2+ elevations under physiological circumstances. To address this question we used mouse sciatic nerve slices, Ca2+ indicator Oregon Green BAPTA-1, and 2-photon Ca2+ imaging in fast line scan mode (500 Hz). We report that transient increases in intra-axonal Ca2+ concentration take place along peripheral nerve axons in situ when axons are stimulated electrically with single pulses. Furthermore, we show for the first time that Ca2+ transients in peripheral nerves are fast, i.e., occur in a millisecond time-domain. Combining Ca2+ imaging and pharmacology with specific blockers of different VGCCs subtypes we demonstrate that Ca2+ transients in peripheral nerves are mediated mainly by N-type and L-type VGCCs. Discovery of fast Ca2+ entry into the axonal shafts through VGCCs in peripheral nerves suggests that Ca2+ may be involved in regulation of action potential propagation and/or properties in this system, or mediate neurotransmitter release along peripheral axons as it occurs in the optic nerve and white matter of the central nervous system (CNS). PMID:27313508

  1. Fibrin glue repair leads to enhanced axonal elongation during early peripheral nerve regeneration in an in vivo mouse model.

    PubMed

    Koulaxouzidis, Georgios; Reim, Gernot; Witzel, Christian

    2015-07-01

    Microsurgical suturing is the gold standard of nerve coaptation. Although literature on the usefulness of fibrin glue as an alternative is becoming increasingly available, it remains contradictory. Furthermore, no data exist on how both repair methods might influence the morphological aspects (arborization; branching) of early peripheral nerve regeneration. We used the sciatic nerve transplantation model in thy-1 yellow fluorescent protein mice (YFP; n = 10). Pieces of nerve (1cm) were grafted from YFP-negative mice (n = 10) into those expressing YFP. We performed microsuture coaptations on one side and used fibrin glue for repair on the contralateral side. Seven days after grafting, the regeneration distance, the percentage of regenerating and arborizing axons, the number of branches per axon, the coaptation failure rate, the gap size at the repair site and the time needed for surgical repair were all investigated. Fibrin glue repair resulted in regenerating axons travelling further into the distal nerve. It also increased the percentage of arborizing axons. No coaptation failure was detected. Gap sizes were comparable in both groups. Fibrin glue significantly reduced surgical repair time. The increase in regeneration distance, even after the short period of time, is in line with the results of others that showed faster axonal regeneration after fibrin glue repair. The increase in arborizing axons could be another explanation for better functional and electrophysiological results after fibrin glue repair. Fibrin glue nerve coaptation seems to be a promising alternative to microsuture repair.

  2. Immunohistological demonstration of CaV3.2 T-type voltage-gated calcium channel expression in soma of dorsal root ganglion neurons and peripheral axons of rat and mouse

    PubMed Central

    Rose, Kirstin E.; Lunardi, Nadia; Boscolo, Annalisa; Dong, Xinzhong; Erisir, Alev; Jevtovic-Todorovic, Vesna; Todorovic, Slobodan M.

    2013-01-01

    Previous behavioural studies have revealed that CaV3.2 T-type calcium channels support peripheral nociceptive transmission and electrophysiological studies have established the presence of T-currents in putative nociceptive sensory neurons of dorsal root ganglion (DRG). To date, however, the localization pattern of this key nociceptive channel in the soma and peripheral axons of these cells has not been demonstrated due to lack of isoform-selective anti-CaV3.2 antibodies. In the present study a new polyclonal CaV3.2 antibody is used to localize CaV3.2 expression in rodent DRG neurons using different staining techniques including confocal and electron microscopy. Confocal microscopy of both acutely dissociated cells and short-term cultures demonstrated strong immunofluorescence of anti-CaV3.2 antibody that was largely confined to smaller diameter DRG neurons where it co-localized with established immuno-markers of unmyelinated nociceptors, such as, CGRP, IB4 and peripherin. In contrast, a smaller proportion of these CaV3.2-labeled DRG cells also co-expressed NF-200, a marker of myelinated sensory neurons. In the rat sciatic nerve preparation, confocal microscopy demonstrated anti-CaV3.2 immunofluorescence which was co-localized with both peripherin and NF-200. Further, electron microscopy revealed immuno-gold labelling of CaV3.2 preferentially in association with un-myelinated sensory fibres from mouse sciatic nerve. Finally, we demonstrated the expression of CaV3.2 channels in peripheral nerve endings of mouse hindpaw skin as shown by co-localisation with Mrgpd-GFP-positive fibres. The CaV3.2 expression within the soma and peripheral axons of nociceptive sensory neurons further demonstrates the importance of this channel in peripheral pain transmission. PMID:23867767

  3. Sensory recovery after cell therapy in peripheral nerve repair: effects of naïve and skin precursor-derived Schwann cells.

    PubMed

    Shakhbazau, Antos; Mohanty, Chandan; Kumar, Ranjan; Midha, Rajiv

    2014-08-01

    Cell therapy is a promising candidate among biological or technological innovations sought to augment microsurgical techniques in peripheral nerve repair. This report describes long-term functional regenerative effects of cell therapy in the rat injury model with a focus on sensory recovery. Schwann cells were derived from isogenic nerve or skin precursor cells and injected into the transected and immediately repaired sciatic nerve distal to the injury site. Sensory recovery was assessed at weeks 4, 7, and 10. Axonal regeneration was assessed at Week 11. By Week 10, thermal sensitivity in cell therapy groups returned to a level indistinguishable from the baseline (p > 0.05). Immunohistochemistry at 11 weeks after injury showed improved regeneration of NF+ and IB4+ axons. The results of this study show that cell therapy significantly improves thermal sensation and the number of regenerated sensory neurons at 11 weeks after injury. These findings contribute to the view of skin-derived stem cells as a reliable source of Schwann cells with therapeutic potential for functional recovery in damaged peripheral nerve.

  4. Clinical evaluation of a new device in the assessment of peripheral sensory neuropathy in diabetes.

    PubMed

    Bracewell, N; Game, F; Jeffcoate, W; Scammell, B E

    2012-12-01

    Current National Institute for Health and Clinical Excellence guidelines state that patients with diabetes should have annual examination of their feet to exclude signs of sensory impairment. The VibraTip is a new disposable device producing a vibratory stimulus, which has been developed in order to screen for peripheral sensory neuropathy in diabetes. This study was designed to evaluate the device by assessing intra-rater reliability and comparing the ability of the VibraTip to detect or exclude peripheral sensory neuropathy with other bedside methods. One hundred and forty-one patients with diabetes (Type 1 or Type 2) were examined for diabetic peripheral sensory neuropathy using a Neurothesiometer, 10-g monofilament, a 128-Hz tuning fork, a Neurotip™ and a VibraTip. The failure to perceive the Neurosthesiometer stimulus at ≥ 25 V in either foot was considered the reference method for the presence of peripheral sensory neuropathy. Receiver operating characteristic curves were produced for each device and the sensitivity, specificity, predictive values and likelihood ratios for the diagnosis of peripheral sensory neuropathy were calculated. Repeat testing with the VibraTip was performed in 18 patients and intra-rater reliability assessed using Cronbach alpha. Analysis of the area under the receiver operating characteristic curves showed that the 10-g monofilament was significantly better than the 128-Hz tuning fork (P = 0.0056) and the Neurotip (P = 0.0022), but was no different from the VibraTip (P = 0.3214). The alpha coefficient for the VibraTip was calculated to be 0.882, indicating good reliability. The VibraTip is a device comparable with the 10-g monofilament and therefore could be considered a useful tool for screening for peripheral sensory neuropathy in diabetes. © 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.

  5. An experimental study of retrograde axonal plasmatic flow in the peripheral nerves of rats.

    PubMed

    Sanguinetti, C; Tranquilli Leali, P; Grispigni, C

    1986-12-01

    Retrograde axonal flow (R.A.F.) in the sciatic nerve of Sprague Dowley rats was studied by injecting horseradish peroxidase (H.R.P.) peripherally and identifying its appearance in the related segment of the spinal cord. This called for a precise identification of the vertebro-medullary topography, the afferant root levels of the sciatic nerve, and the transport velocity of the H.R.P. Our study revealed a clear difference of neuromuscular end plate permeability as between new-born and adult animals. The vertebral column of the rat consists of 8 cervical metameres, 13 dorsal, 6 lumbar, 4 sacral, and 3 coccygeal. The sciatic nerve is derived principally from the roots L4, L5, L6 and in part from L3 and S1. The injection of H.R.P. in the sural triceps of the new-born rat produced granules in the anterior horn cells as early as 12 hours later. In similar experiments with adult rats H.R.P. in the motorneurons was never detected. In our experimental model the transport velocity of H.R.P. from the point of injection to the anterior horn cells was approximately 68 mm per day. These findings provide a foundation on which to base future studies of retrograde flows in conditions of induced pathology.

  6. Ectopic vesicular neurotransmitter release along sensory axons mediates neurovascular coupling via glial calcium signaling.

    PubMed

    Thyssen, Anne; Hirnet, Daniela; Wolburg, Hartwig; Schmalzing, Günther; Deitmer, Joachim W; Lohr, Christian

    2010-08-24

    Neurotransmitter release generally is considered to occur at active zones of synapses, and ectopic release of neurotransmitters has been demonstrated in a few instances. However, the mechanism of ectopic neurotransmitter release is poorly understood. We took advantage of the intimate morphological and functional proximity of olfactory receptor axons and specialized glial cells, olfactory ensheathing cells (OECs), to study ectopic neurotransmitter release. Axonal stimulation evoked purinergic and glutamatergic Ca(2+) responses in OECs, indicating ATP and glutamate release. In axons expressing synapto-pHluorin, stimulation evoked an increase in synapto-pHluorin fluorescence, indicative of vesicle fusion. Transmitter release was dependent on Ca(2+) and could be inhibited by bafilomycin A1 and botulinum toxin A. Ca(2+) transients in OECs evoked by ATP, axonal stimulation, and laser photolysis of NP-EGTA resulted in constriction of adjacent blood vessels. Our results indicate that ATP and glutamate are released ectopically by vesicles along axons and mediate neurovascular coupling via glial Ca(2+) signaling.

  7. Neuronal injury increases retrograde axonal transport of the neurotrophins to spinal sensory neurons and motor neurons via multiple receptor mechanisms.

    PubMed

    Curtis, R; Tonra, J R; Stark, J L; Adryan, K M; Park, J S; Cliffer, K D; Lindsay, R M; DiStefano, P S

    1998-10-01

    We investigated the retrograde axonal transport of 125I-labeled neurotrophins (NGF, BDNF, NT-3, and NT-4) from the sciatic nerve to dorsal root ganglion (DRG) sensory neurons and spinal motor neurons in normal rats or after neuronal injury. DRG neurons showed increased transport of all neurotrophins following crush injury to the sciatic nerve. This was maximal 1 day after sciatic nerve crush and returned to control levels after 7 days. 125I-BDNF transport from sciatic nerve was elevated with injection either proximal to the lesion or directly into the crush site and after transection of the dorsal roots. All neurotrophin transport was receptor-mediated and consistent with neurotrophin binding to the low-affinity neurotrophin receptor (LNR) or Trk receptors. However, transport of 125I-labeled wheat germ agglutinin also increased 1 day after sciatic nerve crush, showing that increased uptake and transport is a generalized response to injury in DRG sensory neurons. Spinal cord motor neurons also showed increased neurotrophin transport following sciatic nerve injury, although this was maximal after 3 days. The transport of 125I-NGF depended on the expression of LNR by injured motor neurons, as demonstrated by competition experiments with unlabeled neurotrophins. The absence of TrkA in normal motor neurons or after axotomy was confirmed by immunostaining and in situ hybridization. Thus, increased transport of neurotrophic factors after neuronal injury is due to multiple receptor-mediated mechanisms including general increases in axonal transport capacity. Copyright 1998 Academic Press.

  8. A quantitative sensory analysis of peripheral neuropathy in colorectal cancer and its exacerbation by oxaliplatin chemotherapy.

    PubMed

    de Carvalho Barbosa, Mariana; Kosturakis, Alyssa K; Eng, Cathy; Wendelschafer-Crabb, Gwen; Kennedy, William R; Simone, Donald A; Wang, Xin S; Cleeland, Charles S; Dougherty, Patrick M

    2014-11-01

    Peripheral neuropathy caused by cytotoxic chemotherapy, especially platins and taxanes, is a widespread problem among cancer survivors that is likely to continue to expand in the future. However, little work to date has focused on understanding this challenge. The goal in this study was to determine the impact of colorectal cancer and cumulative chemotherapeutic dose on sensory function to gain mechanistic insight into the subtypes of primary afferent fibers damaged by chemotherapy. Patients with colorectal cancer underwent quantitative sensory testing before and then prior to each cycle of oxaliplatin. These data were compared with those from 47 age- and sex-matched healthy volunteers. Patients showed significant subclinical deficits in sensory function before any therapy compared with healthy volunteers, and they became more pronounced in patients who received chemotherapy. Sensory modalities that involved large Aβ myelinated fibers and unmyelinated C fibers were most affected by chemotherapy, whereas sensory modalities conveyed by thinly myelinated Aδ fibers were less sensitive to chemotherapy. Patients with baseline sensory deficits went on to develop more symptom complaints during chemotherapy than those who had no baseline deficit. Patients who were tested again 6 to 12 months after chemotherapy presented with the most numbness and pain and also the most pronounced sensory deficits. Our results illuminate a mechanistic connection between the pattern of effects on sensory function and the nerve fiber types that appear to be most vulnerable to chemotherapy-induced toxicity, with implications for how to focus future work to ameloirate risks of peripheral neuropathy.

  9. Peripheral sensory coding through oscillatory synchrony in weakly electric fish

    PubMed Central

    Baker, Christa A; Huck, Kevin R; Carlson, Bruce A

    2015-01-01

    Adaptations to an organism's environment often involve sensory system modifications. In this study, we address how evolutionary divergence in sensory perception relates to the physiological coding of stimuli. Mormyrid fishes that can detect subtle variations in electric communication signals encode signal waveform into spike-timing differences between sensory receptors. In contrast, the receptors of species insensitive to waveform variation produce spontaneously oscillating potentials. We found that oscillating receptors respond to electric pulses by resetting their phase, resulting in transient synchrony among receptors that encodes signal timing and location, but not waveform. These receptors were most sensitive to frequencies found only in the collective signals of groups of conspecifics, and this was correlated with increased behavioral responses to these frequencies. Thus, different perceptual capabilities correspond to different receptor physiologies. We hypothesize that these divergent mechanisms represent adaptations for different social environments. Our findings provide the first evidence for sensory coding through oscillatory synchrony. DOI: http://dx.doi.org/10.7554/eLife.08163.001 PMID:26238277

  10. Autosomal recessive peripheral sensory neuropathy in 3 non-Ashkenazi Jewish families.

    PubMed Central

    Tamari, I; Goodman, R M; Sarova, I; Hertz, M; Adar, R; Zvibach, T

    1980-01-01

    Three unrelated Oriental Jewish families with a total of eight subjects with progressive hereditary sensory neuropathy are reported. The parents were all unaffected and because of parental consanguinity in each of the three families it is postulated that this rare neurological disorder is transmitted in an autosomal recessive manner. In one family both parents showed an abnormal response to pain stimulation with normal motor and sensory nerve conduction velocity. This response may be an expression of the carrier state for this hereditary disease. Only five other families (non-Jewish) have been reported as having this form of peripheral hereditary sensory neuropathy. These observations suggest that one type, the progressive form, of peripheral hereditary sensory neuropathy may be more common in Oriental Jews. Images PMID:6937618

  11. Enhanced axon outgrowth and improved long-distance axon regeneration in sprouty2 deficient mice.

    PubMed

    Marvaldi, Letizia; Thongrong, Sitthisak; Kozłowska, Anna; Irschick, Regina; Pritz, Christian O; Bäumer, Bastian; Ronchi, Giulia; Geuna, Stefano; Hausott, Barbara; Klimaschewski, Lars

    2015-03-01

    Sprouty (Spry) proteins are negative feedback inhibitors of receptor tyrosine kinase signaling. Downregulation of Spry2 has been demonstrated to promote elongative axon growth of cultured peripheral and central neurons. Here, we analyzed Spry2 global knockout mice with respect to axon outgrowth in vitro and peripheral axon regeneration in vivo. Neurons dissociated from adult Spry2 deficient sensory ganglia revealed stronger extracellular signal-regulated kinase activation and enhanced axon outgrowth. Prominent axon elongation was observed in heterozygous Spry2(+/-) neuron cultures, whereas homozygous Spry2(-/-) neurons predominantly exhibited a branching phenotype. Following sciatic nerve crush, Spry2(+/-) mice recovered faster in motor but not sensory testing paradigms (Spry2(-/-) mice did not tolerate anesthesia required for nerve surgery). We attribute the improvement in the rotarod test to higher numbers of myelinated fibers in the regenerating sciatic nerve, higher densities of motor endplates in hind limb muscles and increased levels of GAP-43 mRNA, a downstream target of extracellular regulated kinase signaling. Conversely, homozygous Spry2(-/-) mice revealed enhanced mechanosensory function (von Frey's test) that was accompanied by an increased innervation of the epidermis, elevated numbers of nonmyelinated axons and more IB4-positive neurons in dorsal root ganglia. The present results corroborate the functional significance of receptor tyrosine kinase signaling inhibitors for axon outgrowth during development and nerve regeneration and propose Spry2 as a novel potential target for pharmacological inhibition to accelerate long-distance axon regeneration in injured peripheral nerves.

  12. Peripheral multidendritic sensory neurons are necessary for rhythmic locomotion behavior in Drosophila larvae

    PubMed Central

    Song, Wei; Onishi, Maika; Jan, Lily Yeh; Jan, Yuh Nung

    2007-01-01

    From breathing to walking, rhythmic movements encompass physiological processes important across the entire animal kingdom. It is thought by many that the generation of rhythmic behavior is operated by a central pattern generator (CPG) and does not require peripheral sensory input. Sensory feedback is, however, required to modify or coordinate the motor activity in response to the circumstances of actual movement. In contrast to this notion, we report here that sensory input is necessary for the generation of Drosophila larval locomotion, a form of rhythmic behavior. Blockage of all peripheral sensory inputs resulted in cessation of larval crawling. By conditionally silencing various subsets of larval peripheral sensory neurons, we identified the multiple dendritic (MD) neurons as the neurons essential for the generation of rhythmic peristaltic locomotion. By recording the locomotive motor activities, we further demonstrate that removal of MD neuron input disrupted rhythmic motor firing pattern in a way that prolonged the stereotyped segmental motor firing duration and prevented the propagation of posterior to anterior segmental motor firing. These findings reveal that MD sensory neuron input is a necessary component in the neural circuitry that generates larval locomotion. PMID:17360325

  13. Nocistatin sensitizes TRPA1 channels in peripheral sensory neurons.

    PubMed

    Avenali, Luca; Abate Fulas, Oli; Sondermann, Julia; Narayanan, Pratibha; Gomez-Varela, David; Schmidt, Manuela

    2017-01-02

    The ability of sensory neurons to detect potentially harmful stimuli relies on specialized molecular signal detectors such as transient receptor potential (TRP) A1 ion channels. TRPA1 is critically implicated in vertebrate nociception and different pain states. Furthermore, TRPA1 channels are subject to extensive modulation and regulation - processes which consequently affect nociceptive signaling. Here we show that the neuropeptide Nocistatin sensitizes TRPA1-dependent calcium influx upon application of the TRPA1 agonist mustard oil (MO) in cultured sensory neurons of dorsal root ganglia (DRG). Interestingly, TRPV1-mediated cellular calcium responses are unaffected by Nocistatin. Furthermore, Nocistatin-induced TRPA1-sensitization is likely independent of the Nocistatin binding partner 4-Nitrophenylphosphatase domain and non-neuronal SNAP25-like protein homolog 1 (NIPSNAP1) as assessed by siRNA-mediated knockdown in DRG cultures. In conclusion, we uncovered the sensitization of TRPA1 by Nocistatin, which may represent a novel mechanism how Nocistatin can modulate pain.

  14. The dynein inhibitor Ciliobrevin D inhibits the bidirectional transport of organelles along sensory axons and impairs NGF-mediated regulation of growth cones and axon branches.

    PubMed

    Sainath, Rajiv; Gallo, Gianluca

    2015-07-01

    The axonal transport of organelles is critical for the development, maintenance, and survival of neurons, and its dysfunction has been implicated in several neurodegenerative diseases. Retrograde axon transport is mediated by the motor protein dynein. In this study, using embryonic chicken dorsal root ganglion neurons, we investigate the effects of Ciliobrevin D, a pharmacological dynein inhibitor, on the transport of axonal organelles, axon extension, nerve growth factor (NGF)-induced branching and growth cone expansion, and axon thinning in response to actin filament depolymerization. Live imaging of mitochondria, lysosomes, and Golgi-derived vesicles in axons revealed that both the retrograde and anterograde transport of these organelles was inhibited by treatment with Ciliobrevin D. Treatment with Ciliobrevin D reversibly inhibits axon extension and transport, with effects detectable within the first 20 min of treatment. NGF induces growth cone expansion, axonal filopodia formation and branching. Ciliobrevin D prevented NGF-induced formation of axonal filopodia and branching but not growth cone expansion. Finally, we report that the retrograde reorganization of the axonal cytoplasm which occurs on actin filament depolymerization is inhibited by treatment with Ciliobrevin D, indicating a role for microtubule based transport in this process, as well as Ciliobrevin D accelerating Wallerian degeneration. This study identifies Ciliobrevin D as an inhibitor of the bidirectional transport of multiple axonal organelles, indicating this drug may be a valuable tool for both the study of dynein function and a first pass analysis of the role of axonal transport.

  15. Peripheral neuropathic pain: a mechanism-related organizing principle based on sensory profiles.

    PubMed

    Baron, Ralf; Maier, Christoph; Attal, Nadine; Binder, Andreas; Bouhassira, Didier; Cruccu, Giorgio; Finnerup, Nanna B; Haanpää, Maija; Hansson, Per; Hüllemann, Philipp; Jensen, Troels S; Freynhagen, Rainer; Kennedy, Jeffrey D; Magerl, Walter; Mainka, Tina; Reimer, Maren; Rice, Andrew S C; Segerdahl, Märta; Serra, Jordi; Sindrup, Sören; Sommer, Claudia; Tölle, Thomas; Vollert, Jan; Treede, Rolf-Detlef

    2017-02-01

    Patients with neuropathic pain are heterogeneous in etiology, pathophysiology, and clinical appearance. They exhibit a variety of pain-related sensory symptoms and signs (sensory profile). Different sensory profiles might indicate different classes of neurobiological mechanisms, and hence subgroups with different sensory profiles might respond differently to treatment. The aim of the investigation was to identify subgroups in a large sample of patients with neuropathic pain using hypothesis-free statistical methods on the database of 3 large multinational research networks (German Research Network on Neuropathic Pain (DFNS), IMI-Europain, and Neuropain). Standardized quantitative sensory testing was used in 902 (test cohort) and 233 (validation cohort) patients with peripheral neuropathic pain of different etiologies. For subgrouping, we performed a cluster analysis using 13 quantitative sensory testing parameters. Three distinct subgroups with characteristic sensory profiles were identified and replicated. Cluster 1 (sensory loss, 42%) showed a loss of small and large fiber function in combination with paradoxical heat sensations. Cluster 2 (thermal hyperalgesia, 33%) was characterized by preserved sensory functions in combination with heat and cold hyperalgesia and mild dynamic mechanical allodynia. Cluster 3 (mechanical hyperalgesia, 24%) was characterized by a loss of small fiber function in combination with pinprick hyperalgesia and dynamic mechanical allodynia. All clusters occurred across etiologies but frequencies differed. We present a new approach of subgrouping patients with peripheral neuropathic pain of different etiologies according to intrinsic sensory profiles. These 3 profiles may be related to pathophysiological mechanisms and may be useful in clinical trial design to enrich the study population for treatment responders.

  16. Peripheral neuropathic pain: a mechanism-related organizing principle based on sensory profiles

    PubMed Central

    Baron, Ralf; Maier, Christoph; Attal, Nadine; Binder, Andreas; Bouhassira, Didier; Cruccu, Giorgio; Finnerup, Nanna B.; Haanpää, Maija; Hansson, Per; Hüllemann, Philipp; Jensen, Troels S.; Freynhagen, Rainer; Kennedy, Jeffrey D.; Magerl, Walter; Mainka, Tina; Reimer, Maren; Rice, Andrew S.C.; Segerdahl, Märta; Serra, Jordi; Sindrup, Sören; Sommer, Claudia; Tölle, Thomas; Vollert, Jan; Treede, Rolf-Detlef

    2016-01-01

    Abstract Patients with neuropathic pain are heterogeneous in etiology, pathophysiology, and clinical appearance. They exhibit a variety of pain-related sensory symptoms and signs (sensory profile). Different sensory profiles might indicate different classes of neurobiological mechanisms, and hence subgroups with different sensory profiles might respond differently to treatment. The aim of the investigation was to identify subgroups in a large sample of patients with neuropathic pain using hypothesis-free statistical methods on the database of 3 large multinational research networks (German Research Network on Neuropathic Pain (DFNS), IMI-Europain, and Neuropain). Standardized quantitative sensory testing was used in 902 (test cohort) and 233 (validation cohort) patients with peripheral neuropathic pain of different etiologies. For subgrouping, we performed a cluster analysis using 13 quantitative sensory testing parameters. Three distinct subgroups with characteristic sensory profiles were identified and replicated. Cluster 1 (sensory loss, 42%) showed a loss of small and large fiber function in combination with paradoxical heat sensations. Cluster 2 (thermal hyperalgesia, 33%) was characterized by preserved sensory functions in combination with heat and cold hyperalgesia and mild dynamic mechanical allodynia. Cluster 3 (mechanical hyperalgesia, 24%) was characterized by a loss of small fiber function in combination with pinprick hyperalgesia and dynamic mechanical allodynia. All clusters occurred across etiologies but frequencies differed. We present a new approach of subgrouping patients with peripheral neuropathic pain of different etiologies according to intrinsic sensory profiles. These 3 profiles may be related to pathophysiological mechanisms and may be useful in clinical trial design to enrich the study population for treatment responders. PMID:27893485

  17. Axon reflex in ocular injury: sensory mediation of the response of the rabbit eye to laser irradiation of the iris.

    PubMed

    Butler, J M; Unger, W G; Cole, D F

    1980-10-01

    Laser irradiation of the rabbit iris produces an injury response consisting of prolonged miosis, uveal vasodilation and a transient rise of intraocular pressure (IOP) accompanied by a breakdown of the blood-aqueous barrier. This response has hitherto been attributed partly to prostaglandin (PG) mediation and partly to mediation by a non-cholinergic nervous pathway thought to be sensory in fuction. Responses of the rabbit eye to laser irritation were examined at specified intervals after diathermic coagulation of the epigasserian nerve tract. Both the intensity of the pupillary constriction and the increase in IOP were almost unaltered at 90 minutes but progressively decreased until at 4 days there was essentially no response to high energy laser irradiation in the denervated eye. It was evident that manifestation of the response is largely dependent upon the presence of intact and functional sensory nerves, and it is proposed that endogenous PGs exert some, if not all of their effects via sensory nerve endings. It is suggested that those terminals which are directly stimulated, whether by laser irradiation or by PGs formed during the injury, release some mediator to cause pupillary constriction. From thes terminals impulses pass orthodromically and antidromically by axon reflex to release further mediator from terminals in the region of the ciliary vessels or the major arterial circle. In this way the response is propagated and augmented.

  18. Gravity receptors - An ultrastructural basis for peripheral sensory processing

    NASA Technical Reports Server (NTRS)

    Ross, M. D.; Donovan, K.

    1984-01-01

    The present ultrastructural study of serial sections has shown that type II hair cells of the anterior part of the utricular macula are integrated into the afferent neural circuitry of type I cells, which are arranged in clusters. Additionally, there exists a complex system of intramacularly originating efferent-type nerve fibers and terminals. The findings, taken together, suggest that on morphological grounds, complex processing of sensory information occurs in gravity receptors. Asymmetry of such a complex system may contribute to motion and space-motion sickness.

  19. Laminin gamma1 is critical for Schwann cell differentiation, axon myelination, and regeneration in the peripheral nerve.

    PubMed

    Chen, Zu-Lin; Strickland, Sidney

    2003-11-24

    Laminins are heterotrimeric extracellular matrix proteins that regulate cell viability and function. Laminin-2, composed of alpha2, beta1, and gamma1 chains, is a major matrix component of the peripheral nervous system (PNS). To investigate the role of laminin in the PNS, we used the Cre-loxP system to disrupt the laminin gamma1 gene in Schwann cells. These mice have dramatically reduced expression of laminin gamma1 in Schwann cells, which results in a similar reduction in laminin alpha2 and beta1 chains. These mice exhibit motor defects which lead to hind leg paralysis and tremor. During development, Schwann cells that lack laminin gamma1 were present in peripheral nerves, and proliferated and underwent apoptosis similar to control mice. However, they were unable to differentiate and synthesize myelin proteins, and therefore unable to sort and myelinate axons. In mutant mice, after sciatic nerve crush, the axons showed impaired regeneration. These experiments demonstrate that laminin is an essential component for axon myelination and regeneration in the PNS.

  20. Peripheral sensory neuropathy is associated with altered postocclusive reactive hyperemia in the diabetic foot.

    PubMed

    Barwick, Alex L; Tessier, John W; Janse de Jonge, Xanne; Ivers, James R; Chuter, Vivienne H

    2016-01-01

    This study examined whether the presence of peripheral sensory neuropathy or cardiac autonomic deficits is associated with postocclusive reactive hyperemia (reflective of microvascular function) in the diabetic foot. 99 participants with type 2 diabetes were recruited into this cross-sectional study. The presence of peripheral sensory neuropathy was determined with standard clinical tests and cardiac autonomic function was assessed with heart rate variation testing. Postocclusive reactive hyperemia was measured with laser Doppler in the hallux. Multiple hierarchical regression was performed to examine relationships between neuropathy and the peak perfusion following occlusion and the time to reach this peak. Peripheral sensory neuropathy predicted 22% of the variance in time to peak following occlusion (p<0.05), being associated with a slower time to peak but was not associated with the magnitude of the peak. Heart rate variation was not associated with the postocclusive reactive hyperemia response. This study found an association between the presence of peripheral sensory neuropathy in people with diabetes and altered microvascular reactivity in the lower limb.

  1. Peripheral sensory neuropathy is associated with altered postocclusive reactive hyperemia in the diabetic foot

    PubMed Central

    Barwick, Alex L; Tessier, John W; Janse de Jonge, Xanne; Ivers, James R; Chuter, Vivienne H

    2016-01-01

    Objective This study examined whether the presence of peripheral sensory neuropathy or cardiac autonomic deficits is associated with postocclusive reactive hyperemia (reflective of microvascular function) in the diabetic foot. Research design and methods 99 participants with type 2 diabetes were recruited into this cross-sectional study. The presence of peripheral sensory neuropathy was determined with standard clinical tests and cardiac autonomic function was assessed with heart rate variation testing. Postocclusive reactive hyperemia was measured with laser Doppler in the hallux. Multiple hierarchical regression was performed to examine relationships between neuropathy and the peak perfusion following occlusion and the time to reach this peak. Results Peripheral sensory neuropathy predicted 22% of the variance in time to peak following occlusion (p<0.05), being associated with a slower time to peak but was not associated with the magnitude of the peak. Heart rate variation was not associated with the postocclusive reactive hyperemia response. Conclusions This study found an association between the presence of peripheral sensory neuropathy in people with diabetes and altered microvascular reactivity in the lower limb. PMID:27486520

  2. Early Electrodiagnostic Features of Upper Extremity Sensory Nerves Can Differentiate Axonal Guillain-Barré Syndrome from Acute Inflammatory Demyelinating Polyneuropathy

    PubMed Central

    Koo, Yong Seo; Shin, Ha Young; Kim, Jong Kuk; Nam, Tai-Seung; Shin, Kyong Jin; Bae, Jong-Seok; Suh, Bum Chun; Oh, Jeeyoung; Yoon, Byeol-A

    2016-01-01

    Background and Purpose Serial nerve conduction studies (NCSs) are recommended for differentiating axonal and demyelinating Guillain-Barré syndrome (GBS), but this approach is not suitable for early diagnoses. This study was designed to identify possible NCS parameters for differentiating GBS subtypes. Methods We retrospectively reviewed the medical records of 70 patients with GBS who underwent NCS within 10 days of symptom onset. Patients with axonal GBS and acute inflammatory demyelinating polyneuropathy (AIDP) were selected based on clinical characteristics and serial NCSs. An antiganglioside antibody study was used to increase the diagnostic certainty. Results The amplitudes of median and ulnar nerve sensory nerve action potentials (SNAPs) were significantly smaller in the AIDP group than in the axonal-GBS group. Classification and regression-tree analysis revealed that the distal ulnar sensory nerve SNAP amplitude was the best predictor of axonal GBS. Conclusions Early upper extremity sensory NCS findings are helpful in differentiating axonal-GBS patients with antiganglioside antibodies from AIDP patients. PMID:27819421

  3. Acute motor and sensory axonal neuropathy related to treatment with MEK inhibitors in a patient with advanced melanoma.

    PubMed

    Taha, Tarek; Tzuk-Shina, Tzahala; Forschner, Itay; Bar-Sela, Gil

    2017-09-01

    Approximately one-half of advanced cutaneous melanomas have a V600 mutation in the BRAF gene that activates the mitogen-activated protein kinase pathway. The combination of BRAF plus MEK inhibitors is one of the most effective treatments for these patients. Severe neurological toxicities have been reported in the literature. However, these toxicities are very rare. Here, we present one patient with acute motor and sensory axonal neuropathy, which is a subtype of Guillain-Barre syndrome, secondary to treatment with MEK inhibitors. This side effect had never been described as related to these agents. However, the mitogen-activated protein kinase pathway can be involved in Guillain-Barre syndrome, and awareness of early neurological injury signs is important in patients treated with MEK inhibitors.

  4. A fatal case of seronegative, late-onset systemic lupus erythematosus presenting with motor sensory axonal polyneuropathy.

    PubMed

    Anyfantakis, Dimitrios; Symvoulakis, Emmanouil K; Barbounakis, Emmanouil; Kastanakis, Miltiades; Athanasakis, Evangelos; Blevrakis, Evangelos; Kastanakis, Serafeim

    2014-09-01

    Systemic lupus erythematosus is a multisystemic, autoimmune, inflammatory disorder predominantly affecting young females. Its onset may be abrupt or insidious, presenting with a broad range of clinical and immunological features. We report an unusual case of elderly-onset systemic lupus erythematosus in a woman initially diagnosed with discoid lupus, and subsequently admitted to hospital due to a progressive psycho-motor deficit. Electrophysiological measurements suggested a diagnosis of acute motor sensory axonal neuropathy. Unusual clinical features and negative serology led to diagnostic uncertainty. This case report offers information on the course of the disease through the entire chain of the health care delivery (from primary to tertiary). Despite the efforts of the hospital staff, it was not possible to save the life of the woman.

  5. CMV-associated axonal sensory-motor Guillain-Barré syndrome in a child: Case report and review of the literature.

    PubMed

    Spagnoli, Carlotta; Iodice, Alessandro; Salerno, Grazia Gabriella; Frattini, Daniele; Bertani, Gianna; Pisani, Francesco; Fusco, Carlo

    2016-01-01

    Guillain-Barré syndrome is the most frequent cause of flaccid paresis in Western countries. Moreover, CMV infection is the most common antecedent viral infection in adult patients and the presence of specific IGM antiganglioside antibodies is often identified. Instead, Guillain-Barré syndrome following CMV infections is rarely reported in childhood and often presents severe symptoms at onset and longer recovery times. One year of clinical, electrophysiological and serological follow-up of a 9-year old child with axonal sensory-motor Guillain-Barré syndrome following CMV infection is reported. Moreover, the literature data on paediatric sensory-motor axonal GBS and GBS secondary to CMV infection and antiganglioside antibodies are reviewed. Our patient presented with paraesthesias and a pattern of weakness showing proximal predominance and affecting the upper limbs more than the lower limbs. At nadir, unilateral facial palsy was also present and he was unable to walk. Electroneurography showed motor-sensory axonal damage. Both anti-CMV and anti-GM2 IgM were positive. After early treatment with IVIG and IV methylprednisolone the patient recovered deambulation. Six months later, his neurological examination was normal and electroneurography showed normal data. The sensory-motor axonal form of Guillain-Barré syndrome following CMV infection may present a good prognosis and a prompt full recovery also in children, if adequate treatment is started in time. Copyright © 2015 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

  6. Atf3 mutant mice show reduced axon regeneration and impaired regeneration-associated gene induction after peripheral nerve injury

    PubMed Central

    Gey, Manuel; Wanner, Renate; Schilling, Corinna; Pedro, Maria T.; Sinske, Daniela

    2016-01-01

    Axon injury in the peripheral nervous system (PNS) induces a regeneration-associated gene (RAG) response. Atf3 (activating transcription factor 3) is such a RAG and ATF3's transcriptional activity might induce ‘effector’ RAGs (e.g. small proline rich protein 1a (Sprr1a), Galanin (Gal), growth-associated protein 43 (Gap43)) facilitating peripheral axon regeneration. We provide a first analysis of Atf3 mouse mutants in peripheral nerve regeneration. In Atf3 mutant mice, facial nerve regeneration and neurite outgrowth of adult ATF3-deficient primary dorsal root ganglia neurons was decreased. Using genome-wide transcriptomics, we identified a neuropeptide-encoding RAG cluster (vasoactive intestinal peptide (Vip), Ngf, Grp, Gal, Pacap) regulated by ATF3. Exogenous administration of neuropeptides enhanced neurite growth of Atf3 mutant mice suggesting that these molecules might be effector RAGs of ATF3's pro-regenerative function. In addition to the induction of growth-promoting molecules, we present data that ATF3 suppresses growth-inhibiting molecules such as chemokine (C-C motif) ligand 2. In summary, we show a pro-regenerative ATF3 function during PNS nerve regeneration involving transcriptional activation of a neuropeptide-encoding RAG cluster. ATF3 is a general injury-inducible factor, therefore ATF3-mediated mechanisms identified herein might apply to other cell and injury types. PMID:27581653

  7. Targeted axonal import (TAxI) peptide delivers functional proteins into spinal cord motor neurons after peripheral administration

    PubMed Central

    Sellers, Drew L.; Bergen, Jamie M.; Johnson, Russell N.; Back, Heidi; Ravits, John M.; Horner, Philip J.; Pun, Suzie H.

    2016-01-01

    A significant unmet need in treating neurodegenerative disease is effective methods for delivery of biologic drugs, such as peptides, proteins, or nucleic acids into the central nervous system (CNS). To date, there are no operative technologies for the delivery of macromolecular drugs to the CNS via peripheral administration routes. Using an in vivo phage-display screen, we identify a peptide, targeted axonal import (TAxI), that enriched recombinant bacteriophage accumulation and delivered protein cargo into spinal cord motor neurons after intramuscular injection. In animals with transected peripheral nerve roots, TAxI delivery into motor neurons after peripheral administration was inhibited, suggesting a retrograde axonal transport mechanism for delivery into the CNS. Notably, TAxI-Cre recombinase fusion proteins induced selective recombination and tdTomato-reporter expression in motor neurons after intramuscular injections. Furthermore, TAxI peptide was shown to label motor neurons in the human tissue. The demonstration of a nonviral-mediated delivery of functional proteins into the spinal cord establishes the clinical potential of this technology for minimally invasive administration of CNS-targeted therapeutics. PMID:26888285

  8. Targeted axonal import (TAxI) peptide delivers functional proteins into spinal cord motor neurons after peripheral administration.

    PubMed

    Sellers, Drew L; Bergen, Jamie M; Johnson, Russell N; Back, Heidi; Ravits, John M; Horner, Philip J; Pun, Suzie H

    2016-03-01

    A significant unmet need in treating neurodegenerative disease is effective methods for delivery of biologic drugs, such as peptides, proteins, or nucleic acids into the central nervous system (CNS). To date, there are no operative technologies for the delivery of macromolecular drugs to the CNS via peripheral administration routes. Using an in vivo phage-display screen, we identify a peptide, targeted axonal import (TAxI), that enriched recombinant bacteriophage accumulation and delivered protein cargo into spinal cord motor neurons after intramuscular injection. In animals with transected peripheral nerve roots, TAxI delivery into motor neurons after peripheral administration was inhibited, suggesting a retrograde axonal transport mechanism for delivery into the CNS. Notably, TAxI-Cre recombinase fusion proteins induced selective recombination and tdTomato-reporter expression in motor neurons after intramuscular injections. Furthermore, TAxI peptide was shown to label motor neurons in the human tissue. The demonstration of a nonviral-mediated delivery of functional proteins into the spinal cord establishes the clinical potential of this technology for minimally invasive administration of CNS-targeted therapeutics.

  9. Deletion of Nrf2 impairs functional recovery, reduces clearance of myelin debris and decreases axonal remyelination after peripheral nerve injury

    PubMed Central

    Zhang, Linxia; Johnson, Delinda; Johnson, Jeffrey A.

    2013-01-01

    Oxidative stress is generated in several peripheral nerve injury models. In response to oxidative stress, the transcription factor Nrf2 is activated to induce expression of antioxidant responsive element (ARE) genes. The role of Nrf2 in peripheral nerve injury has not been studied to date. In this study, we used a sciatic nerve crush model to examine how deletion of Nrf2 affects peripheral nerve degeneration and regeneration. Our study demonstrated that functional recovery in the Nrf2-/- mice were impaired compared to the wild type mice after sciatic nerve crush. Larger myelin debris were present in the distal nerve stump of the Nrf2-/- mice than in the wild type mice. The presence of larger myelin debris in the Nrf2-/- mice coincides with less macrophages accumulation in the distal nerve stump. Less accumulation of macrophages may have contributed to slower clearance of myelin and thus resulted in the presence of larger myelin debris. Meanwhile, axonal regeneration is comparatively lower in the Nrf2-/- mice than in the wild type mice. Even after 3 months post the injury, more thinly myelinated axon fibers were present in the Nrf2-/- mice than in the wild type mice. Taken collectively, these data support the concept of therapeutic intervention with Nrf2 activators following nerve injury. PMID:23328769

  10. Kv7.2 regulates the function of peripheral sensory neurons

    PubMed Central

    King, Chih H.; Lancaster, Eric; Salomon, Daniela; Peles, Elior; Scherer, Steven S.

    2014-01-01

    The Kv7 (KCNQ) family of voltage-gated K+ channels regulates cellular excitability. The functional role of Kv7.2 has been hampered by the lack of a viable Kcnq2-null animal model. In this study, we generated homozygous Kcnq2-null sensory neurons using the Cre-Lox system; in these mice, Kv7.2 expression is absent in the peripheral sensory neurons, whereas the expression of other molecular components of nodes (including Kv7.3), paranodes, and juxtaparanodes is not altered. The conditional Kcnq2-null animals exhibit normal motor performance, but have increased thermal hyperalgesia and mechanical allodynia. Whole cell patch recording technique demonstrates that Kcnq2-null sensory neurons have increased excitability and reduced spike frequency adaptation. Taken together, our results suggest that the loss of Kv7.2 activity increases the excitability of primary sensory neurons. PMID:24687876

  11. Overexpression of GAP-43 in thalamic projection neurons of transgenic mice does not enable them to regenerate axons through peripheral nerve grafts.

    PubMed

    Mason, M R; Campbell, G; Caroni, P; Anderson, P N; Lieberman, A R

    2000-09-01

    It is well established that some populations of neurons of the adult rat central nervous system (CNS) will regenerate axons into a peripheral nerve implant, but others, including most thalamocortical projection neurons, will not. The ability to regenerate axons may depend on whether neurons can express growth-related genes such as GAP-43, whose expression correlates with axon growth during development and with competence to regenerate. Thalamic projection neurons which fail to regenerate into a graft also fail to upregulate GAP-43. We have tested the hypothesis that the absence of strong GAP-43 expression by the thalamic projection neurons prevents them from regenerating their axons, using transgenic mice which overexpress GAP-43. Transgene expression was mapped by in situ hybridization with a digoxigenin-labeled RNA probe and by immunohistochemistry with a monoclonal antibody against the GAP-43 protein produced by the transgene. Many CNS neurons were found to express the mRNA and protein, including neurons of the mediodorsal and ventromedial thalamic nuclei, which rarely regenerate axons into peripheral nerve grafts. Grafts were implanted into the region of these nuclei in the brains of transgenic animals. Although these neurons strongly expressed the transgene mRNA and protein and transported the protein to their axon terminals, they did not regenerate axons into the graft, suggesting that lack of GAP-43 expression is not the only factor preventing thalamocortical neurons regenerating their axons. Copyright 2000 Academic Press.

  12. Regeneration of Drosophila sensory neuron axons and dendrites is regulated by the Akt pathway involving Pten and microRNA bantam

    PubMed Central

    Song, Yuanquan; Ori-McKenney, Kassandra M.; Zheng, Yi; Han, Chun; Jan, Lily Yeh; Jan, Yuh Nung

    2012-01-01

    Both cell-intrinsic and extrinsic pathways govern axon regeneration, but only a limited number of factors have been identified and it is not clear to what extent axon regeneration is evolutionarily conserved. Whether dendrites also regenerate is unknown. Here we report that, like the axons of mammalian sensory neurons, the axons of certain Drosophila dendritic arborization (da) neurons are capable of substantial regeneration in the periphery but not in the CNS, and activating the Akt pathway enhances axon regeneration in the CNS. Moreover, those da neurons capable of axon regeneration also display dendrite regeneration, which is cell type-specific, developmentally regulated, and associated with microtubule polarity reversal. Dendrite regeneration is restrained via inhibition of the Akt pathway in da neurons by the epithelial cell-derived microRNA bantam but is facilitated by cell-autonomous activation of the Akt pathway. Our study begins to reveal mechanisms for dendrite regeneration, which depends on both extrinsic and intrinsic factors, including the PTEN–Akt pathway that is also important for axon regeneration. We thus established an important new model system—the fly da neuron regeneration model that resembles the mammalian injury model—with which to study and gain novel insights into the regeneration machinery. PMID:22759636

  13. Slits and Robo-2 regulate the coalescence of subsets of olfactory sensory neuron axons within the ventral region of the olfactory bulb.

    PubMed

    Cho, Jin H; Kam, Joseph W K; Cloutier, Jean-François

    2012-11-15

    Olfactory sensory neurons (OSNs) project their axons to second-order neurons in the olfactory bulb (OB) to form a precise glomerular map and these stereotypic connections are crucial for accurate odorant information processing by animals. To form these connections, olfactory sensory neuron (OSN) axons respond to axon guidance molecules that direct their growth and coalescence. We have previously implicated the axon guidance receptor Robo-2 in the accurate coalescence of OSN axons within the dorsal region of the OB (Cho et al., 2011). Herein, we have examined whether Robo-2 and its ligands, the Slits, contribute to the formation of an accurate glomerular map within more ventral regions of the OB. We have ablated expression of Robo-2 in OSNs and assessed the targeting accuracy of axons expressing either the P2 or MOR28 olfactory receptors, which innervate two different regions of the ventral OB. We show that P2-positive axons, which express Robo-2, coalesce into glomeruli more ventrally and form additional glomeruli in the OB of robo-2(lox/lox);OMP-Cre mice. We also demonstrate that Robo-2-mediated targeting of P2 axons along the dorsoventral axis of the OB is controlled by Slit-1 and Slit-3 expression. Interestingly, although MOR28-positive OSNs only express low levels of Robo-2, a reduced number of MOR28-positive glomeruli is observed in the OB of robo-2(lox/lox);OMP-Cre mice. Taken together, our results demonstrate that Slits and Robo-2 are required for the formation of an accurate glomerular map in the ventral region of the OB.

  14. Chondroitinase C Selectively Degrades Chondroitin Sulfate Glycosaminoglycans that Inhibit Axonal Growth within the Endoneurium of Peripheral Nerve

    PubMed Central

    2016-01-01

    The success of peripheral nerve regeneration is highly dependent on the regrowth of axons within the endoneurial basal lamina tubes that promote target-oriented pathfinding and appropriate reinnervation. Restoration of nerve continuity at this structural level after nerve transection injury by direct repair and nerve grafting remains a major surgical challenge. Recently, biological approaches that alter the balance of growth inhibitors and promoters in nerve have shown promise to improve appropriate axonal regeneration and recovery of peripheral nerve function. Chondroitin sulfate proteoglycans (CSPGs) are known inhibitors of axonal growth. This growth inhibition is mainly associated with a CSPG's glycosaminoglycan chains. Enzymatic degradation of these chains with chondroitinase eliminates this inhibitory activity and, when applied in vivo, can improve the outcome of nerve repair. To date, these encouraging findings were obtained with chondroitinase ABC (a pan-specific chondroitinase). The aim of this study was to examine the distribution of CSPG subtypes in rodent, rabbit, and human peripheral nerve and to test more selective biological enzymatic approaches to improve appropriate axonal growth within the endoneurium and minimize aberrant growth. Here we provide evidence that the endoneurium, but not the surrounding epineurium, is rich in CSPGs that have glycosaminoglycan chains readily degraded by chondroitinase C. Biochemical studies indicate that chondroitinase C has degradation specificity for 6-sulfated glycosaminoglycans found in peripheral nerve. We found that chondroitinase C degrades and inactivates inhibitory CSPGs within the endoneurium but not so much in the surrounding nerve compartments. Cryoculture bioassays (neurons grown on tissue sections) show that chondroitinase C selectively and significantly enhanced neuritic growth associated with the endoneurial basal laminae without changing growth-inhibiting properties of the surrounding epineurium

  15. Sensory signs in complex regional pain syndrome and peripheral nerve injury.

    PubMed

    Gierthmühlen, Janne; Maier, Christoph; Baron, Ralf; Tölle, Thomas; Treede, Rolf-Detlef; Birbaumer, Niels; Huge, Volker; Koroschetz, Jana; Krumova, Elena K; Lauchart, Meike; Maihöfner, Christian; Richter, Helmut; Westermann, Andrea

    2012-04-01

    This study determined patterns of sensory signs in complex regional pain syndrome (CRPS) type I and II and peripheral nerve injury (PNI). Patients with upper-limb CRPS-I (n=298), CRPS-II (n=46), and PNI (n=72) were examined with quantitative sensory testing according to the protocol of the German Research Network on Neuropathic Pain. The majority of patients (66%-69%) exhibited a combination of sensory loss and gain. Patients with CRPS-I had more sensory gain (heat and pressure pain) and less sensory loss than patients with PNI (thermal and mechanical detection, hypoalgesia to heat or pinprick). CRPS-II patients shared features of CRPS-I and PNI. CRPS-I and CRPS-II had almost identical somatosensory profiles, with the exception of a stronger loss of mechanical detection in CRPS-II. In CRPS-I and -II, cold hyperalgesia/allodynia (28%-31%) and dynamic mechanical allodynia (24%-28%) were less frequent than heat or pressure hyperalgesia (36%-44%, 67%-73%), and mechanical hypoesthesia (31%-55%) was more frequent than thermal hypoesthesia (30%-44%). About 82% of PNI patients had at least one type of sensory gain. QST demonstrates more sensory loss in CRPS-I than hitherto considered, suggesting either minimal nerve injury or central inhibition. Sensory profiles suggest that CRPS-I and CRPS-II may represent one disease continuum. However, in contrast to recent suggestions, small fiber deficits were less frequent than large fiber deficits. Sensory gain is highly prevalent in PNI, indicating a better similarity of animal models to human patients than previously thought. These sensory profiles should help prioritize approaches for translation between animal and human research. Copyright © 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

  16. Soluble complement receptor 1 protects the peripheral nerve from early axon loss after injury.

    PubMed

    Ramaglia, Valeria; Wolterman, Ruud; de Kok, Maryla; Vigar, Miriam Ann; Wagenaar-Bos, Ineke; King, Rosalind Helen Mary; Morgan, Brian Paul; Baas, Frank

    2008-04-01

    Complement activation is a crucial early event in Wallerian degeneration. In this study we show that treatment of rats with soluble complement receptor 1 (sCR1), an inhibitor of all complement pathways, blocked both systemic and local complement activation after crush injury of the sciatic nerve. Deposition of membrane attack complex (MAC) in the nerve was inhibited, the nerve was protected from axonal and myelin breakdown at 3 days after injury, and macrophage infiltration and activation was strongly reduced. We show that both classical and alternative complement pathways are activated after acute nerve trauma. Inhibition of the classical pathway by C1 inhibitor (Cetor) diminished, but did not completely block, MAC deposition in the injured nerve, blocked myelin breakdown, inhibited macrophage infiltration, and prevented macrophage activation at 3 days after injury. However, in contrast to sCR1 treatment, early signs of axonal degradation were visible in the nerve, linking MAC deposition to axonal damage. We conclude that sCR1 protects the nerve from early axon loss after injury and propose complement inhibition as a potential therapy for the treatment of diseases in which axon loss is the main cause of disabilities.

  17. ChR2 transgenic animals in peripheral sensory system: Sensing light as various sensations.

    PubMed

    Ji, Zhi-Gang; Wang, Hongxia

    2016-04-01

    Since the introduction of Channelrhodopsin-2 (ChR2) to neuroscience, optogenetics technology was developed, making it possible to activate specific neurons or circuits with spatial and temporal precision. Various ChR2 transgenic animal models have been generated and are playing important roles in revealing the mechanisms of neural activities, mapping neural circuits, controlling the behaviors of animals as well as exploring new strategy for treating the neurological diseases in both central and peripheral nervous system. An animal including humans senses environments through Aristotle's five senses (sight, hearing, smell, taste and touch). Usually, each sense is associated with a kind of sensory organ (eyes, ears, nose, tongue and skin). Is it possible that one could hear light, smell light, taste light and touch light? When ChR2 is targeted to different peripheral sensory neurons by viral vectors or generating ChR2 transgenic animals, the animals can sense the light as various sensations such as hearing, touch, pain, smell and taste. In this review, we focus on ChR2 transgenic animals in the peripheral nervous system. Firstly the working principle of ChR2 as an optogenetic actuator is simply described. Then the current transgenic animal lines where ChR2 was expressed in peripheral sensory neurons are presented and the findings obtained by these animal models are reviewed. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Exogenous BDNF enhances the integration of chronically injured axons that regenerate through a peripheral nerve grafted into a chondroitinase-treated spinal cord injury site.

    PubMed

    Tom, Veronica J; Sandrow-Feinberg, Harra R; Miller, Kassi; Domitrovich, Cheryl; Bouyer, Julien; Zhukareva, Victoria; Klaw, Michelle C; Lemay, Michel A; Houlé, John D

    2013-01-01

    Although axons lose some of their intrinsic capacity for growth after their developmental period, some axons retain the potential for regrowth after injury. When provided with a growth-promoting substrate such as a peripheral nerve graft (PNG), severed axons regenerate into and through the graft; however, they stop when they reach the glial scar at the distal graft-host interface that is rich with inhibitory chondroitin sulfate proteoglycans. We previously showed that treatment of a spinal cord injury site with chondroitinase (ChABC) allows axons within the graft to traverse the scar and reinnervate spinal cord, where they form functional synapses. While this improvement in outgrowth was significant, it still represented only a small percentage (<20%) of axons compared to the total number of axons that regenerated into the PNG. Here we tested whether providing exogenous brain-derived neurotrophic factor (BDNF) via lentivirus in tissue distal to the PNG would augment regeneration beyond a ChABC-treated glial interface. We found that ChABC treatment alone promoted axonal regeneration but combining ChABC with BDNF-lentivirus did not increase the number of axons that regenerated back into spinal cord. Combining BDNF with ChABC did increase the number of spinal cord neurons that were trans-synaptically activated during electrical stimulation of the graft, as indicated by c-Fos expression, suggesting that BDNF overexpression improved the functional significance of axons that did reinnervate distal spinal cord tissue. Copyright © 2012 Elsevier Inc. All rights reserved.

  19. Exogenous BDNF enhances the integration of chronically injured axons that regenerate through a peripheral nerve grafted into a chondroitinase-treated spinal cord injury site

    PubMed Central

    Tom, Veronica J.; Sandrow-Feinberg, Harra R.; Miller, Kassi; Domitrovich, Cheryl; Bouyer, Julien; Zhukareva, Victoria; Klaw, Michelle C.; Lemay, Michel A.; Houlé, John D.

    2016-01-01

    Although axons lose some of their intrinsic capacity for growth after their developmental period, some axons retain the potential for regrowth after injury. When provided with a growth-promoting substrate such as a peripheral nerve graft (PNG), severed axons regenerate into and through the graft; however, they stop when they reach the glial scar at the distal graft-host interface that is rich with inhibitory chondroitin sulfate proteoglycans. We previously showed that treatment of a spinal cord injury site with chondroitinase (ChABC) allows axons within the graft to traverse the scar and reinnervate spinal cord, where they form functional synapses. While this improvement in outgrowth was significant, it still represented only a small percentage (<20%) of axons compared to the total number of axons that regenerated into the PNG. Here we tested whether providing exogenous brain-derived neurotrophic factor (BDNF) via lentivirus in tissue distal to the PNG would augment regeneration beyond a ChABC-treated glial interface. We found that ChABC treatment alone promoted axonal regeneration but combining ChABC with BDNF-lentivirus did not increase the number of axons that regenerated back into spinal cord. Combining BDNF with ChABC did increase the number of spinal cord neurons that were trans-synaptically activated during electrical stimulation of the graft, as indicated by c-Fos expression, suggesting that BDNF overexpression improved the functional significance of axons that did reinnervate distal spinal cord tissue. PMID:23022460

  20. Stereoselective peripheral sensory neurotoxicity of diaminocyclohexane platinum enantiomers related to ormaplatin and oxaliplatin.

    PubMed Central

    Screnci, D.; Er, H. M.; Hambley, T. W.; Galettis, P.; Brouwer, W.; McKeage, M. J.

    1997-01-01

    The diaminocyclohexane platinum (Pt(DACH)) derivatives ormaplatin and oxaliplatin have caused severe and dose-limiting peripheral sensory neurotoxicity in a clinical trial. We hypothesized that this toxicity could vary in relation to the biotransformation and stereochemistry of these Pt(DACH) derivatives. We prepared pure R,R and S,S enantiomers of ormaplatin (Pt(DACH)Cl4), oxaliplatin (Pt(DACH)oxalato) and their metabolites (Pt(DACH)Cl2 and Pt(DACH)methionine) and assessed their peripheral sensory neurotoxicity and tissue distribution in the rat and in vitro anti-tumour activity in human ovarian carcinoma cell lines. The R,R enantiomers of Pt(DACH)Cl4, Pt(DACH)oxalato and Pt(DACH)Cl2, induced peripheral sensory neurotoxicity at significantly lower cumulative doses (18 +/- 5.7 vs 32 +/- 2.3 micromol kg(-1); P < 0.01) and at earlier times (4 +/- 1 vs 6.7 +/- 0.6 weeks; P = 0.016) during repeat-dose treatment than the S,S enantiomers. Pt(DACH)methionine enantiomers showed no biological activity. There was no difference between Pt(DACH) enantiomers in the platinum concentration in sciatic nerve, dorsal root ganglia, spinal cord, brain or blood at the end of each experiment. Three human ovarian carcinoma cell lines (41 M, 41 McisR and SKOV-3) showed no (or inconsistent) chiral discrimination in their sensitivity to Pt(DACH) enantiomers, whereas two cell lines (CH-1 and CH-1cisR) showed modest enantiomeric selectivity favouring the R,R isomer (more active). In conclusion, Pt(DACH) derivatives exhibit enantiomeric-selective peripheral sensory neurotoxicity during repeated dosing in rats favouring S,S isomers (less neurotoxic). They exhibited less chiral discrimination in their accumulation within peripheral nerves and in vitro anti-tumour activity. PMID:9275028

  1. Integrin-linked kinase is required for radial sorting of axons and Schwann cell remyelination in the peripheral nervous system

    PubMed Central

    Pereira, Jorge A.; Benninger, Yves; Baumann, Reto; Gonçalves, Ana Filipa; Özçelik, Murat; Thurnherr, Tina; Tricaud, Nicolas; Meijer, Dies; Fässler, Reinhard; Suter, Ueli

    2009-01-01

    During development, Schwann cells (SCs) interpret different extracellular cues to regulate their migration, proliferation, and the remarkable morphological changes associated with the sorting, ensheathment, and myelination of axons. Although interactions between extracellular matrix proteins and integrins are critical to some of these processes, the downstream signaling pathways they control are still poorly understood. Integrin-linked kinase (ILK) is a focal adhesion protein that associates with multiple binding partners to link integrins to the actin cytoskeleton and is thought to participate in integrin and growth factor–mediated signaling. Using SC-specific gene ablation, we report essential functions for ILK in radial sorting of axon bundles and in remyelination in the peripheral nervous system. Our in vivo and in vitro experiments show that ILK negatively regulates Rho/Rho kinase signaling to promote SC process extension and to initiate radial sorting. ILK also facilitates axon remyelination, likely by promoting the activation of downstream molecules such as AKT/protein kinase B. PMID:19349584

  2. A locus for axonal motor-sensory neuropathy with deafness and mental retardation maps to Xq26-q27

    SciTech Connect

    Priest, J.M.; Nouri, N.; Keats, B.J.B.

    1994-09-01

    Twenty-two DNA markers spanning the X chromosome have been analyzed for linkage to the locus causing an unusual form of X-linked recessive hereditary motor and sensory neuropathy in a Pennsylvania family of Italian ancestry. This 3 generation family which was originally reported by Cowchock includes 7 affected males, 3 obligate carrier females, and 4 unaffected males. Males are severely affected at birth or within the first few years of life with areflexia, slowly progressive axonal atrophy, and absence of large myelinated fibers, and they all develop pes cavus and hammer toes. Five of the 7 affected males show associated deafness and 3 of these 5 individuals also presented with mental retardation or social developmental delay. Motor nerve conduction velocities in affected males are normal to mildly delayed and sensory conduction velocities are markedly abnormal. Heterozygous females are asymptomatic. Close linkage to the Xg blood group locus (Xp22) was previously excluded in this family while weak linkage of the disease gene to DXYS1 (Xq13-q21) was suggested. The current study excludes the short arm and the proximal long arm of the X chromosome. Haplotype analysis of markers on the long arm demonstrates that HPRT is a proximal flanking marker and that the disease gene is closely linked to the marker DXS984. Further microsatellite markers are being studied in order to refine the region of the distal long arm of the X chromosome containing the gene causing the motor-sensory neuropathy in this family. This is the first such gene assigned to the distal region of Xq.

  3. Modality-Specific Axonal Regeneration: Toward Selective Regenerative Neural Interfaces

    PubMed Central

    Lotfi, Parisa; Garde, Kshitija; Chouhan, Amit K.; Bengali, Ebrahim; Romero-Ortega, Mario I.

    2011-01-01

    Regenerative peripheral nerve interfaces have been proposed as viable alternatives for the natural control of robotic prosthetic devices. However, sensory and motor axons at the neural interface are of mixed sub-modality types, which difficult the specific recording from motor axons and the eliciting of precise sensory modalities through selective stimulation. Here we evaluated the possibility of using type specific neurotrophins to preferentially entice the regeneration of defined axonal populations from transected peripheral nerves into separate compartments. Segregation of mixed sensory fibers from dorsal root ganglion neurons was evaluated in vitro by compartmentalized diffusion delivery of nerve growth factor (NGF) and neurotrophin-3 (NT-3), to preferentially entice the growth of TrkA+ nociceptive and TrkC+ proprioceptive subsets of sensory neurons, respectively. The average axon length in the NGF channel increased 2.5-fold compared to that in saline or NT-3, whereas the number of branches increased threefold in the NT-3 channels. These results were confirmed using a 3D “Y”-shaped in vitro assay showing that the arm containing NGF was able to entice a fivefold increase in axonal length of unbranched fibers. To address if such segregation can be enticed in vivo, a “Y”-shaped tubing was used to allow regeneration of the transected adult rat sciatic nerve into separate compartments filled with either NFG or NT-3. A significant increase in the number of CGRP+ pain fibers were attracted toward the sural nerve, while N-52+ large-diameter axons were observed in the tibial and NT-3 compartments. This study demonstrates the guided enrichment of sensory axons in specific regenerative chambers, and supports the notion that neurotrophic factors can be used to segregate sensory and perhaps motor axons in separate peripheral interfaces. PMID:22016734

  4. Effects of Valproic Acid on Axonal Regeneration and Recovery of Motor Function after Peripheral Nerve Injury in the Rat

    PubMed Central

    Rao, Ting; Wu, Fei; Xing, Danmou; Peng, Zhengren; Ren, Dong; Feng, Wei; Chen, Yan; Zhao, Zhiming; Wang, Huan; Wang, Junweng; Kan, Wusheng; Zhang, Qingsong

    2014-01-01

    Background: Valproic acid (VPA) is used to be an effective anti-epileptic drug and mood stabilizer. It has recently been demonstrated that VPA could promote neurite outgrowth, activate the extracellular signal regulated kinase pathway, and increases bcl-2 and growth cone-associated protein 43 levels in spinal cord. In the present research we demonstrate the effect of VPA on peripheral nerve regeneration and recovery of motor function following sciatic nerve transaction in rats. Methods: The rats in VPA group and control group were administered with valproic acid (300mg/kg) and sodium chloride respectively after operation. Each animal was observed sciatic nerve index (SFI) at 2-week intervals and studied electrophysiology at 4-week intervals for 12 weeks. Histological and morphometrical analyses were performed 12 weeks after operation. Using the digital image-analysis system, thickness of the myelin sheath was measured, and total numbers of regenerated axons were counted. Results: There was a significant difference in SFI, electrophysiological index (motor-nerve conduct velocity), and morphometrical results (regenerated axon number and thickness of myelin sheath) in nerve regeneration between the VPA group and controls (P<0.05). Conclusions: The results demonstrated that VPA is able to enhance sciatic nerve regeneration in rats, suggesting the potential clinical application of VPA for the treatment of peripheral nerve injury in humans. PMID:25207308

  5. Charcot-Marie-Tooth 2b associated Rab7 mutations cause axon growth and guidance defects during vertebrate sensory neuron development.

    PubMed

    Ponomareva, Olga Y; Eliceiri, Kevin W; Halloran, Mary C

    2016-01-20

    Charcot-Marie-Tooth2b (CMT2b) is an axonal form of a human neurodegenerative disease that preferentially affects sensory neurons. CMT2b is dominantly inherited and is characterized by unusually early onset, presenting in the second or third decade of life. Five missense mutations in the gene encoding Rab7 GTPase have been identified as causative in human CMT2b disease. Although several studies have modeled CMT2b disease in cultured neurons and in Drosophila, the mechanisms by which defective Rab7 leads to disease remain poorly understood. We used zebrafish to investigate the effects of CMT2b-associated Rab7 mutations in a vertebrate model. We generated transgenic animals expressing the CMT2b-associated mutant forms of Rab7 in sensory neurons, and show that these Rab7 variants cause neurodevelopmental defects, including defects in sensory axon growth, branching and pathfinding at early developmental stages. We also find reduced axon growth and branching in neurons expressing a constitutively active form of Rab7, suggesting these defects may be caused by Rab7 gain-of-function. Further, we use high-speed, high-resolution imaging of endosome transport in vivo and find that CMT2b-associated Rab7 variants cause reduced vesicle speeds, suggesting altered transport may underlie axon development defects. Our data provide new insight into how disease-associated alterations in Rab7 protein disrupt cellular function in vertebrate sensory neurons. Moreover, our findings suggest that defects in axon development may be a previously unrecognized component of CMT2b disease.

  6. Emx2 homeodomain transcription factor interacts with eukaryotic translation initiation factor 4E (eIF4E) in the axons of olfactory sensory neurons.

    PubMed

    Nédélec, Stéphane; Foucher, Isabelle; Brunet, Isabelle; Bouillot, Colette; Prochiantz, Alain; Trembleau, Alain

    2004-07-20

    We report that Emx2 homeogene is expressed at the mRNA and protein levels in the adult mouse olfactory neuroepithelium. As expected for a transcription factor, Emx2 is present in the nucleus of immature and mature olfactory sensory neurons. However, the protein is also detected in the axonal compartment of these neurons, both in the olfactory mucosa axon bundles and in axon terminals within the olfactory bulb. Emx2 axonal staining is heterogeneous, suggesting an association with particles. Subcellular fractionations of olfactory bulb synaptosomes, combined with chemical lesions of olfactory neurons, confirm the presence of Emx2 in axon terminals. Significant amounts of Emx2 protein cosediment with high density synaptosomal subfractions containing eukaryotic translation initiation factor 4E (eIF4E). Nonionic detergents and RNase treatments failed to detach eIF4E and Emx2 from these high-density fractions enriched in vesicles and granular structures. In addition, Emx2 and eIF4E can be coimmunoprecipitated from olfactory mucosa and bulb extracts and interact directly, as demonstrated in pull-down experiments. Emx2 axonal localization, association with high-density particles and interaction with eIF4E strongly suggest that this transcription factor has new nonnuclear functions most probably related to the local control of protein translation in the olfactory sensory neuron axons. Finally, we show that two other brain-expressed homeoproteins, Otx2 and Engrailed 2, also bind eIF4E, indicating that several homeoproteins may modulate eIF4E functions in the developing and adult nervous system.

  7. Multifocal acquired demyelinating sensory and motor neuropathy presenting as a peripheral nerve tumor.

    PubMed

    Allen, David C; Smallman, Clare A; Mills, Kerry R

    2006-09-01

    A man with multifocal acquired demyelinating sensory and motor neuropathy (MADSAM), or Lewis-Sumner syndrome, presented with a progressive left lumbosacral plexus lesion resembling a neurofibroma. After 7 years he developed a left ulnar nerve lesion with conduction block in its upper segment. Treatment with intravenous immunoglobulin improved the symptoms and signs of both lesions. We conclude that inflammatory neuropathy must be considered in the differential diagnosis of peripheral nerve tumors, and that unifocal lesions may precede multifocal involvement in MADSAM by several years. In addition, we discuss the clinical features in 9 patients attending a specialist peripheral nerve clinic and review the literature.

  8. Comparative proteomic analysis of differentially expressed proteins between peripheral sensory and motor nerves.

    PubMed

    He, Qianru; Man, Lili; Ji, Yuhua; Zhang, Shuqiang; Jiang, Maorong; Ding, Fei; Gu, Xiaosong

    2012-06-01

    Peripheral sensory and motor nerves have different functions and different approaches to regeneration, especially their distinct ability to accurately reinervate terminal nerve pathways. To understand the molecular aspects underlying these differences, the proteomics technique by coupling isobaric tags for relative and absolute quantitation (iTRAQ) with online two-dimensional liquid chromatography tandem mass spectrometry (2D LC-MS/MS) was used to investigate the protein profile of sensory and motor nerve samples from rats. A total of 1472 proteins were identified in either sensory or motor nerve. Of them, 100 proteins showed differential expressions between both nerves, and some of them were validated by quantitative real time RT-PCR, Western blot analysis, and immunohistochemistry. In the light of functional categorization, the differentially expressed proteins in sensory and motor nerves, belonging to a broad range of classes, were related to a diverse array of biological functions, which included cell adhesion, cytoskeleton, neuronal plasticity, neurotrophic activity, calcium-binding, signal transduction, transport, enzyme catalysis, lipid metabolism, DNA-binding, synaptosome function, actin-binding, ATP-binding, extracellular matrix, and commitment to other lineages. The relatively higher expressed proteins in either sensory or motor nerve were tentatively discussed in combination with their specific molecular characteristics. It is anticipated that the database generated in this study will provide a solid foundation for further comprehensive investigation of functional differences between sensory and motor nerves, including the specificity of their regeneration.

  9. Rapid alteration of thalamocortical axon morphology follows peripheral damage in the neonatal rat.

    PubMed Central

    Catalano, S M; Robertson, R T; Killackey, H P

    1995-01-01

    The effect of day of birth (postnatal day 0; P0) infraorbital nerve section on the morphology of individual thalamocortical axons in rat somatosensory cortex was examined on P3. Thalamic fibers were labeled in fixed brains with the carbocyanine dye 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate, and individual photo-converted thalamocortical fibers were reconstructed. In normal animals on P3, axon arbor terminal formation within layer IV has commenced and terminal arbor width is comparable to that of a cortical "barrel." After infraorbital nerve section, the average width of thalamocortical terminal arbors is significantly greater than is the average arbor width of normal rats of the same age; however, neither the number of branches per terminal arbor nor total arbor length differs between groups. These observations suggest that the role of the periphery in guiding terminal arbor formation is exerted both very rapidly and at the level of the single thalamic axon. Further, these results indicate a close association between individual axon terminal arbor morphology and pattern formation in the rat somatosensory cortex. Images Fig. 1 PMID:7708683

  10. The effect of intraluminal contact mediated guidance signals on axonal mismatch during peripheral nerve repair.

    PubMed

    Daly, William T; Yao, Li; Abu-rub, Mohammad T; O'Connell, Claire; Zeugolis, Dimitrios I; Windebank, Anthony J; Pandit, Abhay S

    2012-10-01

    The current microsurgical gold standard for repairing long gap nerve injuries is the autograft. Autograft provides a protective environment for repair and a natural internal architecture, which is essential for regeneration. Current clinically approved hollow nerve guidance conduits allow provision of this protective environment; however they fail to provide an essential internal architecture to the regenerating nerve. In the present study both structured and unstructured intraluminal collagen fibres are investigated to assess their ability to enhance conduit mediated nerve repair. This study presents a direct comparison of both structured and unstructured fibres in vivo. The addition of intraluminal guidance structures was shown to significantly decrease axonal dispersion within the conduit and reduced axonal mismatch of distal nerve targets (p < 0.05). The intraluminal fibres were shown to be successfully incorporated into the host regenerative process, acting as a platform for Schwann cell migration and axonal regeneration. Ultimately the fibres were able to provide a platform for nerve regeneration in a long term regeneration study (16 weeks) and facilitated increased guidance of regenerating axons towards their distal nerve targets. Copyright © 2012 Elsevier Ltd. All rights reserved.

  11. A coin-like peripheral small cell lung carcinoma associated with acute paraneoplastic axonal Guillain-Barre-like syndrome.

    PubMed

    Jung, Ioan; Gurzu, Simona; Balasa, Rodica; Motataianu, Anca; Contac, Anca Otilia; Halmaciu, Ioana; Popescu, Septimiu; Simu, Iunius

    2015-06-01

    A 65-year-old previously healthy male heavy smoker was hospitalized with a 2-week history of progressive muscle weakness in the lower and upper extremities. After 10 days of hospitalization, urinary sphincter incompetence and fecal incontinence were added and tetraparesis was established. The computer-tomography scan examination revealed a massive right hydrothorax and multifocal solid acinar structures with peripheral localization in the left lung, which suggested pulmonary cancer. Bone marrow metastases were also suspected. Based on the examination results, the final diagnosis was acute paraneoplastic axonal Guillain-Barre-like syndrome. The patient died 3 weeks after hospitalization. At autopsy, bronchopneumonia and a right hydrothorax were confirmed. Several 4 to 5-mm-sized round peripherally located white nodules were identified in the left lung, without any central tumor mass. Under microscope, a coin-shaped peripheral/subpleural small cell carcinoma was diagnosed, with generalized bone metastases. A huge thrombus in the abdominal aorta and acute pancreatitis was also seen at autopsy. This case highlights the difficulty of diagnosis of lung carcinomas and the necessity of a complex differential diagnosis of severe progressive ascending neuropathies. This is the 6th reported case of small cell lung cancer-associated acute Guillain-Barre-like syndrome and the first report about an association with a coin-like peripheral pattern.

  12. Stratifying patients with peripheral neuropathic pain based on sensory profiles: algorithm and sample size recommendations.

    PubMed

    Vollert, Jan; Maier, Christoph; Attal, Nadine; Bennett, David L H; Bouhassira, Didier; Enax-Krumova, Elena K; Finnerup, Nanna B; Freynhagen, Rainer; Gierthmühlen, Janne; Haanpää, Maija; Hansson, Per; Hüllemann, Philipp; Jensen, Troels S; Magerl, Walter; Ramirez, Juan D; Rice, Andrew S C; Schuh-Hofer, Sigrid; Segerdahl, Märta; Serra, Jordi; Shillo, Pallai R; Sindrup, Soeren; Tesfaye, Solomon; Themistocleous, Andreas C; Tölle, Thomas R; Treede, Rolf-Detlef; Baron, Ralf

    2017-08-01

    In a recent cluster analysis, it has been shown that patients with peripheral neuropathic pain can be grouped into 3 sensory phenotypes based on quantitative sensory testing profiles, which are mainly characterized by either sensory loss, intact sensory function and mild thermal hyperalgesia and/or allodynia, or loss of thermal detection and mild mechanical hyperalgesia and/or allodynia. Here, we present an algorithm for allocation of individual patients to these subgroups. The algorithm is nondeterministic-ie, a patient can be sorted to more than one phenotype-and can separate patients with neuropathic pain from healthy subjects (sensitivity: 78%, specificity: 94%). We evaluated the frequency of each phenotype in a population of patients with painful diabetic polyneuropathy (n = 151), painful peripheral nerve injury (n = 335), and postherpetic neuralgia (n = 97) and propose sample sizes of study populations that need to be screened to reach a subpopulation large enough to conduct a phenotype-stratified study. The most common phenotype in diabetic polyneuropathy was sensory loss (83%), followed by mechanical hyperalgesia (75%) and thermal hyperalgesia (34%, note that percentages are overlapping and not additive). In peripheral nerve injury, frequencies were 37%, 59%, and 50%, and in postherpetic neuralgia, frequencies were 31%, 63%, and 46%. For parallel study design, either the estimated effect size of the treatment needs to be high (>0.7) or only phenotypes that are frequent in the clinical entity under study can realistically be performed. For crossover design, populations under 200 patients screened are sufficient for all phenotypes and clinical entities with a minimum estimated treatment effect size of 0.5.

  13. Stratifying patients with peripheral neuropathic pain based on sensory profiles: algorithm and sample size recommendations

    PubMed Central

    Vollert, Jan; Maier, Christoph; Attal, Nadine; Bennett, David L.H.; Bouhassira, Didier; Enax-Krumova, Elena K.; Finnerup, Nanna B.; Freynhagen, Rainer; Gierthmühlen, Janne; Haanpää, Maija; Hansson, Per; Hüllemann, Philipp; Jensen, Troels S.; Magerl, Walter; Ramirez, Juan D.; Rice, Andrew S.C.; Schuh-Hofer, Sigrid; Segerdahl, Märta; Serra, Jordi; Shillo, Pallai R.; Sindrup, Soeren; Tesfaye, Solomon; Themistocleous, Andreas C.; Tölle, Thomas R.; Treede, Rolf-Detlef; Baron, Ralf

    2017-01-01

    Abstract In a recent cluster analysis, it has been shown that patients with peripheral neuropathic pain can be grouped into 3 sensory phenotypes based on quantitative sensory testing profiles, which are mainly characterized by either sensory loss, intact sensory function and mild thermal hyperalgesia and/or allodynia, or loss of thermal detection and mild mechanical hyperalgesia and/or allodynia. Here, we present an algorithm for allocation of individual patients to these subgroups. The algorithm is nondeterministic—ie, a patient can be sorted to more than one phenotype—and can separate patients with neuropathic pain from healthy subjects (sensitivity: 78%, specificity: 94%). We evaluated the frequency of each phenotype in a population of patients with painful diabetic polyneuropathy (n = 151), painful peripheral nerve injury (n = 335), and postherpetic neuralgia (n = 97) and propose sample sizes of study populations that need to be screened to reach a subpopulation large enough to conduct a phenotype-stratified study. The most common phenotype in diabetic polyneuropathy was sensory loss (83%), followed by mechanical hyperalgesia (75%) and thermal hyperalgesia (34%, note that percentages are overlapping and not additive). In peripheral nerve injury, frequencies were 37%, 59%, and 50%, and in postherpetic neuralgia, frequencies were 31%, 63%, and 46%. For parallel study design, either the estimated effect size of the treatment needs to be high (>0.7) or only phenotypes that are frequent in the clinical entity under study can realistically be performed. For crossover design, populations under 200 patients screened are sufficient for all phenotypes and clinical entities with a minimum estimated treatment effect size of 0.5. PMID:28595241

  14. Peripheral site of action of levodropropizine in experimentally-induced cough: role of sensory neuropeptides.

    PubMed

    Lavezzo, A; Melillo, G; Clavenna, G; Omini, C

    1992-06-01

    The mechanism of action of levodropropizine has been investigated in different models of experimentally-induced cough in guinea-pigs. In particular it has been demonstrated that the antitussive drug has a peripheral site of action by injecting the drug intracerebroventricularly (i.c.v.). In these experiments levodropropizine (40 micrograms/50 microliters i.c.v.) did not prevent electrically-induced cough. On the other hand, codeine (5 micrograms/50 microliters i.c.v.) markedly prevented coughing. A difference in the potency ratio of levodropropizine and codeine has been demonstrated in capsaicin-induced cough; after oral administration, codeine was about two to three times more potent than levodropropizine. However, after aerosol administration the two compounds were equipotent. These data might suggest a peripheral site of action for levodropropizine which is related to sensory neuropeptides. Further support for the role of sensory neuropeptides in the mechanism of action of levodropropizine comes from the results obtained in capsaicin-desensitized animals. In this experimental model levodropropizine failed to prevent the vagally elicited cough in neuropeptide-depleted animals, whereas codeine did not differentiate between control and capsaicin-treated animals. In conclusion, our results support the suggestion that levodropropizine has a peripheral site of action. In addition, the interference with the sensory neuropeptide system may explain, at least in part, its activity in experimentally-induced cough.

  15. Wallerian degeneration of zebrafish trigeminal axons in the skin is required for regeneration and developmental pruning

    PubMed Central

    Martin, Seanna M.; O'Brien, Georgeann S.; Portera-Cailliau, Carlos; Sagasti, Alvaro

    2010-01-01

    Fragments of injured axons that detach from their cell body break down by the molecularly regulated process of Wallerian degeneration (WD). Although WD resembles local axon degeneration, a common mechanism for refining neuronal structure, several previously examined instances of developmental pruning were unaffected by WD pathways. We used laser axotomy and time-lapse confocal imaging to characterize and compare peripheral sensory axon WD and developmental pruning in live zebrafish larvae. Detached fragments of single injured axon arbors underwent three stereotyped phases of WD: a lag phase, a fragmentation phase and clearance. The lag phase was developmentally regulated, becoming shorter as embryos aged, while the length of the clearance phase increased with the amount of axon debris. Both cell-specific inhibition of ubiquitylation and overexpression of the Wallerian degeneration slow protein (WldS) lengthened the lag phase dramatically, but neither affected fragmentation. Persistent WldS-expressing axon fragments directly repelled regenerating axon branches of their parent arbor, similar to self-repulsion among sister branches of intact arbors. Expression of WldS also disrupted naturally occurring local axon pruning and axon degeneration in spontaneously dying trigeminal neurons: although pieces of WldS-expressing axons were pruned, and some WldS-expressing cells still died during development, in both cases detached axon fragments failed to degenerate. We propose that spontaneously pruned fragments of peripheral sensory axons must be removed by a WD-like mechanism to permit efficient innervation of the epidermis. PMID:21041367

  16. Over-expression of alpha-synuclein in the nervous system enhances axonal degeneration after peripheral nerve lesion in a transgenic mouse strain.

    PubMed

    Siebert, Heike; Kahle, Philipp J; Kramer, Michael L; Isik, Thomas; Schlüter, Oliver M; Schulz-Schaeffer, Walter J; Brück, Wolfgang

    2010-08-01

    Wallerian degeneration in peripheral nerves occurs after a traumatic insult when the distal nerve part degenerates while peripheral macrophages enter the nerve stump and remove the accruing debris by phagozytosis. We used an experimental model to investigate the effect of either the absence or over-expression of alpha-synuclein (alpha-syn) after transecting the sciatic nerves of mice. alpha-Synuclein is a major component of Lewy bodies and its aggregation results in a premature destruction of nerve cells. It has also been found present in different peripheral nerves but its role in the axon remains still unclear. Following sciatic nerve transection in different mouse strains, we investigated the numbers of invading macrophages, the amounts of remaining myelin and axons 6 days after injury. All mice showed clear signs of Wallerian degeneration, but transgenic mice expressing human wild-type alpha-syn showed lower numbers of invading macrophages, less preserved myelin and significantly lower numbers of preserved axons in comparison with either knockout mice or a mouse strain with a spontaneous deletion of alpha-syn. The use of protein aggregation filtration blots and paraffin-embedded tissue blots displayed depositions of alpha-syn aggregates within sciatic nerve axons of transgenic mice. Thicker myelin sheaths and higher numbers of mitochondria were detected in old alpha-syn transgenic mice. In a human sural nerve, alpha-syn could also be identified within axons. Thus, alpha-syn and its aggregates are not only a component of Lewy bodies and synapses but also of axons and these aggregates might interfere with axonal transport. alpha-Synuclein transgenic mice represent an appropriate model for investigations on axonal transport in neurodegenerative diseases.

  17. Reversible motor and sensory peripheral neuropathy in a patient following acute carbon monoxide intoxication.

    PubMed

    García, Antonio; Maestro, Iratxe

    2005-01-01

    Central nervous system complications following carbon monoxide (CO) poisoning are well reported in the literature but peripheral neuropathy is under-recognized. We report the clinical and electrophysiological studies of the transient peripheral neuropathy developed in a patient following acute CO intoxication. A 27-year-old woman was found unconscious with severe hypoxia and 34.5% serum level of carboxyhemoglobin. She progressed favourably after hyperbaric oxygen therapy. Neurological examination revealed bilateral pyramidal signs. The patient referred weakness and sensory abnormalities in her right foot. An electroencephalogram did not show focal abnormalities and brain magnetic resonance was normal. Needle electromyography of weak right tibialis anterior muscle showed a reduced recruitment pattern but no spontaneous activity. Electroneurographic evaluation revealed findings compatible with a motor and sensory peripheral neuropathy in nerves of both lower limbs. In few months complete clinical recovery was reached, and the electroneurography showed normality a year later Reversible peripheral neuropathy should be considered as a possible neurological complication following acute CO poisoning. The electrophysiological studies were essential for its diagnosis and follow up.

  18. The prevalence, predictors, and consequences of peripheral sensory neuropathy in older patients.

    PubMed

    Mold, James W; Vesely, Sara K; Keyl, Barbara A; Schenk, Joan B; Roberts, Michelle

    2004-01-01

    The prevalence, predictors, and consequences of peripheral neuropathy in the elderly have not been well defined. Seven hundred ninety-five noninstitutionalized patients 65 years of age and older, recruited from the practices of family physicians, completed questionnaires and underwent peripheral neurologic examinations and tests of gait and balance. Variables included sociodemographic information, medical conditions, symptoms (numbness, pain, trouble with balance or walking, and restless legs), quality of life measures, ankle reflexes, position sense, vibratory sense, fine touch sensation, Tinnetti balance examination, and a 50-foot timed walk. The prevalence of at least one bilateral sensory deficit rose from 26% for 65- to 74-year-olds to 54% for those 85 and older. The most common deficit was loss of ankle reflex followed by loss of fine touch. Only 40% of those with bilateral deficits reported having a disease known to cause peripheral neuropathy. Predictors of bilateral deficits included increasing age, income less than 15,000 dollars, a history of military service, increasing body mass index, self-reported history of diabetes mellitus, Vitamin B12 deficiency or rheumatoid arthritis, and absence of a history of hypertension. Deficits were associated with numbness, pain, restless legs, trouble walking, trouble with balance, and reduced quality of life. Peripheral sensory deficits are common in the elderly. In most cases, a medical cause is not obvious. Their consequences may not be as benign as often supposed.

  19. Expressing Constitutively Active Rheb in Adult Dorsal Root Ganglion Neurons Enhances the Integration of Sensory Axons that Regenerate Across a Chondroitinase-Treated Dorsal Root Entry Zone Following Dorsal Root Crush

    PubMed Central

    Wu, Di; Klaw, Michelle C.; Kholodilov, Nikolai; Burke, Robert E.; Detloff, Megan R.; Côté, Marie-Pascale; Tom, Veronica J.

    2016-01-01

    While the peripheral branch of dorsal root ganglion neurons (DRG) can successfully regenerate after injury, lesioned central branch axons fail to regrow across the dorsal root entry zone (DREZ), the interface between the dorsal root and the spinal cord. This lack of regeneration is due to the limited regenerative capacity of adult sensory axons and the growth-inhibitory environment at the DREZ, which is similar to that found in the glial scar after a central nervous system (CNS) injury. We hypothesized that transduction of adult DRG neurons using adeno-associated virus (AAV) to express a constitutively-active form of the GTPase Rheb (caRheb) will increase their intrinsic growth potential after a dorsal root crush. Additionally, we posited that if we combined that approach with digestion of upregulated chondroitin sulfate proteoglycans (CSPG) at the DREZ with chondroitinase ABC (ChABC), we would promote regeneration of sensory axons across the DREZ into the spinal cord. We first assessed if this strategy promotes neuritic growth in an in vitro model of the glial scar containing CSPG. ChABC allowed for some regeneration across the once potently inhibitory substrate. Combining ChABC treatment with expression of caRheb in DRG significantly improved this growth. We then determined if this combination strategy also enhanced regeneration through the DREZ after dorsal root crush in adult rats in vivo. After unilaterally crushing C4-T1 dorsal roots, we injected AAV5-caRheb or AAV5-GFP into the ipsilateral C5-C8 DRGs. ChABC or PBS was injected into the ipsilateral dorsal horn at C5-C8 to digest CSPG, for a total of four animal groups (caRheb + ChABC, caRheb + PBS, GFP + ChABC, GFP + PBS). Regeneration was rarely observed in PBS-treated animals, whereas short-distance regrowth across the DREZ was observed in ChABC-treated animals. No difference in axon number or length between the ChABC groups was observed, which may be related to intraganglionic inflammation induced by the

  20. Expressing Constitutively Active Rheb in Adult Dorsal Root Ganglion Neurons Enhances the Integration of Sensory Axons that Regenerate Across a Chondroitinase-Treated Dorsal Root Entry Zone Following Dorsal Root Crush.

    PubMed

    Wu, Di; Klaw, Michelle C; Kholodilov, Nikolai; Burke, Robert E; Detloff, Megan R; Côté, Marie-Pascale; Tom, Veronica J

    2016-01-01

    While the peripheral branch of dorsal root ganglion neurons (DRG) can successfully regenerate after injury, lesioned central branch axons fail to regrow across the dorsal root entry zone (DREZ), the interface between the dorsal root and the spinal cord. This lack of regeneration is due to the limited regenerative capacity of adult sensory axons and the growth-inhibitory environment at the DREZ, which is similar to that found in the glial scar after a central nervous system (CNS) injury. We hypothesized that transduction of adult DRG neurons using adeno-associated virus (AAV) to express a constitutively-active form of the GTPase Rheb (caRheb) will increase their intrinsic growth potential after a dorsal root crush. Additionally, we posited that if we combined that approach with digestion of upregulated chondroitin sulfate proteoglycans (CSPG) at the DREZ with chondroitinase ABC (ChABC), we would promote regeneration of sensory axons across the DREZ into the spinal cord. We first assessed if this strategy promotes neuritic growth in an in vitro model of the glial scar containing CSPG. ChABC allowed for some regeneration across the once potently inhibitory substrate. Combining ChABC treatment with expression of caRheb in DRG significantly improved this growth. We then determined if this combination strategy also enhanced regeneration through the DREZ after dorsal root crush in adult rats in vivo. After unilaterally crushing C4-T1 dorsal roots, we injected AAV5-caRheb or AAV5-GFP into the ipsilateral C5-C8 DRGs. ChABC or PBS was injected into the ipsilateral dorsal horn at C5-C8 to digest CSPG, for a total of four animal groups (caRheb + ChABC, caRheb + PBS, GFP + ChABC, GFP + PBS). Regeneration was rarely observed in PBS-treated animals, whereas short-distance regrowth across the DREZ was observed in ChABC-treated animals. No difference in axon number or length between the ChABC groups was observed, which may be related to intraganglionic inflammation induced by the

  1. Adeno-associated Virus Vectors Efficiently Transduce Mouse and Rabbit Sensory Neurons Coinfected with Herpes Simplex Virus 1 following Peripheral Inoculation

    PubMed Central

    Watson, Zachary L.; Ertel, Monica K.; Lewin, Alfred S.; Tuli, Sonal S.; Schultz, Gregory S.; Neumann, Donna M.

    2016-01-01

    ABSTRACT Following infection of epithelial tissues, herpes simplex virus 1 (HSV-1) virions travel via axonal transport to sensory ganglia and establish a lifelong latent infection within neurons. Recent studies have revealed that, following intraganglionic or intrathecal injection, recombinant adeno-associated virus (rAAV) vectors can also infect sensory neurons and are capable of stable, long-term transgene expression. We sought to determine if application of rAAV to peripheral nerve termini at the epithelial surface would allow rAAV to traffic to sensory ganglia in a manner similar to that seen with HSV. We hypothesized that footpad or ocular inoculation with rAAV8 would result in transduction of dorsal root ganglia (DRG) or trigeminal ganglia (TG), respectively. To test this, we inoculated the footpads of mice with various amounts of rAAV as well as rAAV capsid mutants. We demonstrated that this method of inoculation can achieve a transduction rate of >90% of the sensory neurons in the DRG that innervate the footpad. Similarly, we showed that corneal inoculation with rAAV vectors in the rabbit efficiently transduced >70% of the TG neurons in the optic tract. Finally, we demonstrated that coinfection of mouse footpads or rabbit eyes with rAAV vectors and HSV-1 resulted in colocalization in nearly all of the HSV-1-positive neurons. These results suggest that rAAV is a useful tool for the study of HSV-1 infection and may provide a means to deliver therapeutic cargos for the treatment of HSV infections or of dysfunctions of sensory ganglia. IMPORTANCE Adeno-associated virus (AAV) has been shown to transduce dorsal root ganglion sensory neurons following direct intraganglionic sciatic nerve injection and intraperitoneal and intravenous injection as well as intrathecal injection. We sought to determine if rAAV vectors would be delivered to the same sensory neurons that herpes simplex virus (HSV-1) infects when applied peripherally at an epithelial surface that had

  2. Sensory Protection of Rat Muscle Spindles following Peripheral Nerve Injury and Reinnervation

    PubMed Central

    Elsohemy, Amal; Butler, Richard; Bain, James R.; Fahnestock, Margaret

    2012-01-01

    Background Skeletal muscle structure and function are dependent on intact Richard Butler, Ph.D. innervation. Prolonged muscle denervation results in irreversible muscle fiber James R. Bain, M.D. atrophy, connective tissue hyperplasia, and deterioration of muscle spindles, Margaret Fahnestock, Ph.D. specialized sensory receptors necessary for proper skeletal muscle function. The protective effect of temporary sensory innervation on denervated muscle, before motor nerve repair, has been shown in the rat. Sensory-protected muscles exhibit less fiber atrophy and connective tissue hyperplasia and maintain greater functional capacity than denervated muscles. The purpose of this study was to determine whether temporary sensory innervation also protects muscle spindles from degeneration. Methods Rat tibial nerve was transected and repaired with either the saphenous or the original transected nerve. Negative controls remained denervated. After 3 to 6 months, the electrophysiologic response of the nerve to stretch in the rat gastrocnemius muscle was measured (n = 3 per group). After the animals were euthanized, the gastrocnemius muscle was removed, sectioned, stained, and examined for spindle number (n = 3 per group) and morphology (one rat per group). Immunohistochemical assessment of muscle spindle innervation was examined in four additional animals. Results Significant deterioration of muscle spindles was seen in denervated muscle, whereas in muscle reinnervated with the tibial or the saphenous nerve, spindle number and morphology were improved. Histologic and functional evidence of spindle reinnervation by the sensory nerve was obtained. Conclusion These findings add to the known means by which motor or sensory nerves exert protective effects on denervated muscle, and further promote the use of sensory protection for improving the outcome after peripheral nerve injury. PMID:19952642

  3. Developmental localization of calcitonin gene-related peptide in dorsal sensory axons and ventral motor neurons of mouse cervical spinal cord.

    PubMed

    Kim, Jeongtae; Sunagawa, Masanobu; Kobayashi, Shiori; Shin, Taekyun; Takayama, Chitoshi

    2016-04-01

    Calcitonin gene-related peptide (CGRP) is a 37-amino-acid neuropeptide, synthesized by alternative splicing of calcitonin gene mRNA. CGRP is characteristically distributed in the nervous system, and its function varies depending on where it is expressed. To reveal developmental formation of the CGRP network and its function in neuronal maturation, we examined the immunohistochemical localization of CGRP in the developing mouse cervical spinal cord and dorsal root ganglion. CGRP immunolabeling (IL) was first detected in motor neurons on E13, and in ascending axons of the posterior funiculus and DRG neurons on E14. CGRP-positive sensory axon fibers entered Laminae I and II on E16, and Laminae I through IV on E18. The intensity of the CGRP-IL gradually increased in both ventral and dorsal horns during embryonic development, but markedly decreased in the ventral horn after birth. These results suggest that CGRP is expressed several days after neuronal settling and entry of sensory fibers, and that the CGRP network is formed in chronological and sequential order. Furthermore, because CGRP is markedly expressed in motor neurons when axons are vastly extending and innervating targets, CGRP may also be involved in axonal elongation and synapse formation during normal development.

  4. Peripheral Nerve Regeneration and NGF-Dependent Neurite Outgrowth of Adult Sensory Neurons Converge on STAT3 Phosphorylation Downstream of Neuropoietic Cytokine Receptor gp130

    PubMed Central

    Quarta, Serena; Baeumer, Bastian E.; Scherbakov, Nadja; Andratsch, Manfred; Rose-John, Stefan; Dechant, Georg; Bandtlow, Christine E.

    2014-01-01

    After nerve injury, adult sensory neurons can regenerate peripheral axons and reconnect with their target tissue. Initiation of outgrowth, as well as elongation of neurites over long distances, depends on the signaling of receptors for neurotrophic growth factors. Here, we investigated the importance of gp130, the signaling subunit of neuropoietic cytokine receptors in peripheral nerve regeneration. After sciatic nerve crush, functional recovery in vivo was retarded in SNS-gp130−/− mice, which specifically lack gp130 in sensory neurons. Correspondingly, a significantly reduced number of free nerve endings was detected in glabrous skin from SNS-gp130−/− compared with control mice after nerve crush. Neurite outgrowth and STAT3 activation in vitro were severely reduced in cultures in gp130-deficient cultured neurons. Surprisingly, in neurons obtained from SNS-gp130−/− mice the increase in neurite length was reduced not only in response to neuropoietic cytokine ligands of gp130 but also to nerve growth factor (NGF), which does not bind to gp130-containing receptors. Neurite outgrowth in the absence of neurotrophic factors was partially rescued in gp130-deficient neurons by leptin, which activates STAT3 downstream of leptic receptor and independent of gp130. The neurite outgrowth response of gp130-deficient neurons to NGF was fully restored in the presence of leptin. Based on these findings, gp130 signaling via STAT3 activation is suggested not only to be an important regulator of peripheral nerve regeneration in vitro and in vivo, but as determining factor for the growth promoting action of NGF in adult sensory neurons. PMID:25253866

  5. Peripheral nerve regeneration and NGF-dependent neurite outgrowth of adult sensory neurons converge on STAT3 phosphorylation downstream of neuropoietic cytokine receptor gp130.

    PubMed

    Quarta, Serena; Baeumer, Bastian E; Scherbakov, Nadja; Andratsch, Manfred; Rose-John, Stefan; Dechant, Georg; Bandtlow, Christine E; Kress, Michaela

    2014-09-24

    After nerve injury, adult sensory neurons can regenerate peripheral axons and reconnect with their target tissue. Initiation of outgrowth, as well as elongation of neurites over long distances, depends on the signaling of receptors for neurotrophic growth factors. Here, we investigated the importance of gp130, the signaling subunit of neuropoietic cytokine receptors in peripheral nerve regeneration. After sciatic nerve crush, functional recovery in vivo was retarded in SNS-gp130(-/-) mice, which specifically lack gp130 in sensory neurons. Correspondingly, a significantly reduced number of free nerve endings was detected in glabrous skin from SNS-gp130(-/-) compared with control mice after nerve crush. Neurite outgrowth and STAT3 activation in vitro were severely reduced in cultures in gp130-deficient cultured neurons. Surprisingly, in neurons obtained from SNS-gp130(-/-) mice the increase in neurite length was reduced not only in response to neuropoietic cytokine ligands of gp130 but also to nerve growth factor (NGF), which does not bind to gp130-containing receptors. Neurite outgrowth in the absence of neurotrophic factors was partially rescued in gp130-deficient neurons by leptin, which activates STAT3 downstream of leptic receptor and independent of gp130. The neurite outgrowth response of gp130-deficient neurons to NGF was fully restored in the presence of leptin. Based on these findings, gp130 signaling via STAT3 activation is suggested not only to be an important regulator of peripheral nerve regeneration in vitro and in vivo, but as determining factor for the growth promoting action of NGF in adult sensory neurons. Copyright © 2014 the authors 0270-6474/14/3413222-12$15.00/0.

  6. An ENU-induced mutation in mouse glycyl-tRNA synthetase (GARS) causes peripheral sensory and motor phenotypes creating a model of Charcot-Marie-Tooth type 2D peripheral neuropathy

    PubMed Central

    Achilli, Francesca; Bros-Facer, Virginie; Williams, Hazel P.; Banks, Gareth T.; AlQatari, Mona; Chia, Ruth; Tucci, Valter; Groves, Michael; Nickols, Carole D.; Seburn, Kevin L.; Kendall, Rachel; Cader, Muhammed Z.; Talbot, Kevin; van Minnen, Jan; Burgess, Robert W.; Brandner, Sebastian; Martin, Joanne E.; Koltzenburg, Martin; Greensmith, Linda; Nolan, Patrick M.; Fisher, Elizabeth M. C.

    2009-01-01

    SUMMARY Mutations in the enzyme glycyl-tRNA synthetase (GARS) cause motor and sensory axon loss in the peripheral nervous system in humans, described clinically as Charcot-Marie-Tooth type 2D or distal spinal muscular atrophy type V. Here, we characterise a new mouse mutant, GarsC201R, with a point mutation that leads to a non-conservative substitution within GARS. Heterozygous mice with a C3H genetic background have loss of grip strength, decreased motor flexibility and disruption of fine motor control; this relatively mild phenotype is more severe on a C57BL/6 background. Homozygous mutants have a highly deleterious set of features, including movement difficulties and death before weaning. Heterozygous animals have a reduction in axon diameter in peripheral nerves, slowing of nerve conduction and an alteration in the recovery cycle of myelinated axons, as well as innervation defects. An assessment of GARS levels showed increased protein in 15-day-old mice compared with controls; however, this increase was not observed in 3-month-old animals, indicating that GARS function may be more crucial in younger animals. We found that enzyme activity was not reduced detectably in heterozygotes at any age, but was diminished greatly in homozygous mice compared with controls; thus, homozygous animals may suffer from a partial loss of function. The GarsC201R mutation described here is a contribution to our understanding of the mechanism by which mutations in tRNA synthetases, which are fundamentally important, ubiquitously expressed enzymes, cause axonopathy in specific sets of neurons. PMID:19470612

  7. An ENU-induced mutation in mouse glycyl-tRNA synthetase (GARS) causes peripheral sensory and motor phenotypes creating a model of Charcot-Marie-Tooth type 2D peripheral neuropathy.

    PubMed

    Achilli, Francesca; Bros-Facer, Virginie; Williams, Hazel P; Banks, Gareth T; AlQatari, Mona; Chia, Ruth; Tucci, Valter; Groves, Michael; Nickols, Carole D; Seburn, Kevin L; Kendall, Rachel; Cader, Muhammed Z; Talbot, Kevin; van Minnen, Jan; Burgess, Robert W; Brandner, Sebastian; Martin, Joanne E; Koltzenburg, Martin; Greensmith, Linda; Nolan, Patrick M; Fisher, Elizabeth M C

    2009-01-01

    Mutations in the enzyme glycyl-tRNA synthetase (GARS) cause motor and sensory axon loss in the peripheral nervous system in humans, described clinically as Charcot-Marie-Tooth type 2D or distal spinal muscular atrophy type V. Here, we characterise a new mouse mutant, Gars(C201R), with a point mutation that leads to a non-conservative substitution within GARS. Heterozygous mice with a C3H genetic background have loss of grip strength, decreased motor flexibility and disruption of fine motor control; this relatively mild phenotype is more severe on a C57BL/6 background. Homozygous mutants have a highly deleterious set of features, including movement difficulties and death before weaning. Heterozygous animals have a reduction in axon diameter in peripheral nerves, slowing of nerve conduction and an alteration in the recovery cycle of myelinated axons, as well as innervation defects. An assessment of GARS levels showed increased protein in 15-day-old mice compared with controls; however, this increase was not observed in 3-month-old animals, indicating that GARS function may be more crucial in younger animals. We found that enzyme activity was not reduced detectably in heterozygotes at any age, but was diminished greatly in homozygous mice compared with controls; thus, homozygous animals may suffer from a partial loss of function. The Gars(C201R) mutation described here is a contribution to our understanding of the mechanism by which mutations in tRNA synthetases, which are fundamentally important, ubiquitously expressed enzymes, cause axonopathy in specific sets of neurons.

  8. Functional Selectivity of Kappa Opioid Receptor Agonists in Peripheral Sensory Neurons

    PubMed Central

    Jamshidi, Raehannah J.; Jacobs, Blaine A.; Sullivan, Laura C.; Chavera, Teresa A.; Saylor, Rachel M.; Prisinzano, Thomas E.; Clarke, William P.

    2015-01-01

    Activation of kappa opioid receptors (KORs) expressed by peripheral sensory neurons that respond to noxious stimuli (nociceptors) can reduce neurotransmission of pain stimuli from the periphery to the central nervous system. We have previously shown that the antinociception dose-response curve for peripherally restricted doses of the KOR agonist (–)-(trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide (U50488) has an inverted U shape. Here, we found that the downward phase of the U50488 dose-response curve was blocked by an inhibitor of extracellular signal-regulated kinase (ERK) activation U0126. Local administration of the selective KOR agonist salvinorin A (Sal-A), also resulted in an inverted U-shaped curve; however, the downward phase was insensitive to U0126. By contrast, inhibition of c-Jun N-terminal kinase (JNK) partially blocked the downward phase of the dose-response curve to Sal-A, suggesting a role for JNK. In cultures of peripheral sensory neurons, U50488 and Sal-A inhibited adenylyl cyclase activity with similar efficacies; however, their ability to activate ERK and JNK differed. Whereas U50488 activated ERK but not JNK, Sal-A activated JNK but not ERK. Moreover, although both U50488 and Sal-A produced homologous desensitization, desensitization to U50488 was blocked by inhibition of ERK activation, whereas desensitization to Sal-A was blocked by inhibition of JNK. Substitution of an ethoxymethyl ether for the C2 position acetyl group of Sal-A reduced stimulation of JNK, prevented desensitization by ethoxymethyl ether for the C2 position acetyl group of Sal-A, and resulted in a monotonic antinociception dose-response curve. Collectively, these data demonstrate the functional selectivity of KOR ligands for signaling in peripheral sensory neurons, which results in differential effects on behavioral responses in vivo. PMID:26297384

  9. Functional selectivity of kappa opioid receptor agonists in peripheral sensory neurons.

    PubMed

    Jamshidi, Raehannah J; Jacobs, Blaine A; Sullivan, Laura C; Chavera, Teresa A; Saylor, Rachel M; Prisinzano, Thomas E; Clarke, William P; Berg, Kelly A

    2015-11-01

    Activation of kappa opioid receptors (KORs) expressed by peripheral sensory neurons that respond to noxious stimuli (nociceptors) can reduce neurotransmission of pain stimuli from the periphery to the central nervous system. We have previously shown that the antinociception dose-response curve for peripherally restricted doses of the KOR agonist (-)-(trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide (U50488) has an inverted U shape. Here, we found that the downward phase of the U50488 dose-response curve was blocked by an inhibitor of extracellular signal-regulated kinase (ERK) activation U0126. Local administration of the selective KOR agonist salvinorin A (Sal-A), also resulted in an inverted U-shaped curve; however, the downward phase was insensitive to U0126. By contrast, inhibition of c-Jun N-terminal kinase (JNK) partially blocked the downward phase of the dose-response curve to Sal-A, suggesting a role for JNK. In cultures of peripheral sensory neurons, U50488 and Sal-A inhibited adenylyl cyclase activity with similar efficacies; however, their ability to activate ERK and JNK differed. Whereas U50488 activated ERK but not JNK, Sal-A activated JNK but not ERK. Moreover, although both U50488 and Sal-A produced homologous desensitization, desensitization to U50488 was blocked by inhibition of ERK activation, whereas desensitization to Sal-A was blocked by inhibition of JNK. Substitution of an ethoxymethyl ether for the C2 position acetyl group of Sal-A reduced stimulation of JNK, prevented desensitization by ethoxymethyl ether for the C2 position acetyl group of Sal-A, and resulted in a monotonic antinociception dose-response curve. Collectively, these data demonstrate the functional selectivity of KOR ligands for signaling in peripheral sensory neurons, which results in differential effects on behavioral responses in vivo. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

  10. Taste placodes are primary targets of geniculate but not trigeminal sensory axons in mouse developing tongue.

    PubMed

    Mbiene, Joseph-Pascal

    2004-12-01

    Tongue embryonic taste buds begin to differentiate before the onset of gustatory papilla formation in murine. In light of this previous finding, we sought to reexamine the developing sensory innervation as it extends toward the lingual epithelium between E 11.5 and 14.5. Nerve tracings with fluorescent lipophilic dyes followed by confocal microscope examination were used to study the terminal branching of chorda tympani and lingual nerves. At E11.5, we confirmed that the chorda tympani nerve provided for most of the nerve branching in the tongue swellings. At E12.5, we show that the lingual nerve contribution to the overall innervation of the lingual swellings increased to the extent that its ramifications matched those of the chorda tympani nerve. At E13.0, the chorda tympani nerve terminal arborizations appeared more complex than those of the lingual nerve. While the chorda tympani nerve terminal branching appeared close to the lingual epithelium that of the trigeminal nerve remained rather confined to the subepithelial mesenchymal tissue. At E13.5, chorda tympani nerve terminals projected specifically to an ordered set of loci on the tongue dorsum corresponding to the epithelial placodes. In contrast, the lingual nerve terminals remained subepithelial with no branches directed towards the placodes. At E14.5, chorda tympani nerve filopodia first entered the apical epithelium of the developing fungiform papilla. The results suggest that there may be no significant delay between the differentiation of embryonic taste buds and their initial innervation.

  11. The effects of FGF-2 gene therapy combined with voluntary exercise on axonal regeneration across peripheral nerve gaps.

    PubMed

    Haastert, Kirsten; Ying, Zhe; Grothe, Claudia; Gómez-Pinilla, Fernando

    2008-10-10

    Studies were conducted to determine the possibility that voluntary exercise could enhance regenerative effects of gene therapy via Schwann cells (SC) over-expressing FGF-2. Sedentary or exercise rehabilitation conditions were therefore provided shortly after reconstructing 10mm sciatic nerve gaps in rats with silicone grafts. Exercise for 7 days elevated mRNA levels of regeneration associated proteins (GAP-43 and synapsin I) in lumbar spinal cord and dorsal root ganglia of SC transplanted, in contrast to non-cellular reconstructed rats. FGF-2 gene therapy followed by 25-27 days of exercise did enhance regeneration of myelinated axons in comparison to sedentary animals. Four weeks after surgery mRNA levels of regeneration associated proteins were significantly higher in lumbar spinal cord of running compared to sedentary SC transplanted animals. Our results suggest that voluntary exercise could reinforce the beneficial effects of SC transplantation and FGF-2 gene therapy in peripheral nerve reconstruction approaches.

  12. Protons regulate the excitability properties of rat myelinated sensory axons in vitro through block of persistent sodium currents.

    PubMed

    Maurer, Konrad; Bostock, Hugh; Koltzenburg, Martin

    2012-03-01

    Little information is available on the pH sensitivity of the excitability properties of mammalian axons. Computer-assisted threshold tracking in humans has helped to define clinically relevant changes of nerve excitability in response to hyperventilation and ischaemia, but in vivo studies cannot directly differentiate between the impact of pH and other secondary factors. In this investigation, we applied an excitability testing protocol to a rat saphenous skin nerve in vitro preparation. Changes in extracellular pH were induced by altering pCO(2) in the perfusate, and excitability properties of large myelinated fibres were measured in the pH range from 6.9 to 8.1. The main effect of protons on nerve excitability was a near linear increase in threshold which was accompanied by a decrease in strength-duration time constant reflecting mainly a decrease in persistent sodium current. In the recovery cycle, late subexcitability following 7 conditioning stimuli was substantially reduced at acid pH, indicating a block of slow but not of fast potassium channels. Changes in threshold electrotonus were complex, reflecting the combined effects of pH on multiple channel types. These results provide the first systematic data on pH sensitivity of mammalian nerve excitability properties, and may help in the interpretation of abnormal clinical excitability measurements. © 2012 Peripheral Nerve Society.

  13. Delaying the onset of treadmill exercise following peripheral nerve injury has different effects on axon regeneration and motoneuron synaptic plasticity

    PubMed Central

    Brandt, Jaclyn; Evans, Jonathan T.; Mildenhall, Taylor; Mulligan, Amanda; Konieczny, Aimee; Rose, Samuel J.

    2015-01-01

    Transection of a peripheral nerve results in withdrawal of synapses from motoneurons. Some of the withdrawn synapses are restored spontaneously, but those containing the vesicular glutamate transporter 1 (VGLUT1), and arising mainly from primary afferent neurons, are withdrawn permanently. If animals are exercised immediately after nerve injury, regeneration of the damaged axons is enhanced and no withdrawal of synapses from injured motoneurons can be detected. We investigated whether delaying the onset of exercise until after synapse withdrawal had occurred would yield similar results. In Lewis rats, the right sciatic nerve was cut and repaired. Reinnervation of the soleus muscle was monitored until a direct muscle (M) response was observed to stimulation of the tibial nerve. At that time, rats began 2 wk of daily treadmill exercise using an interval training protocol. Both M responses and electrically-evoked H reflexes were monitored weekly for an additional seven wk. Contacts made by structures containing VGLUT1 or glutamic acid decarboxylase (GAD67) with motoneurons were studied from confocal images of retrogradely labeled cells. Timing of full muscle reinnervation was similar in both delayed and immediately exercised rats. H reflex amplitude in delayed exercised rats was only half that found in immediately exercised animals. Unlike immediately exercised animals, motoneuron contacts containing VGLUT1 in delayed exercised rats were reduced significantly, relative to intact rats. The therapeutic window for application of exercise as a treatment to promote restoration of synaptic inputs onto motoneurons following peripheral nerve injury is different from that for promoting axon regeneration in the periphery. PMID:25632080

  14. A system and method to interface with multiple groups of axons in several fascicles of peripheral nerves.

    PubMed

    Thota, Anil K; Kuntaegowdanahalli, Sathyakumar; Starosciak, Amy K; Abbas, James J; Orbay, Jorge; Horch, Kenneth W; Jung, Ranu

    2015-04-15

    Several neural interface technologies that stimulate and/or record from groups of axons have been developed. The longitudinal intrafascicular electrode (LIFE) is a fine wire that can provide access to a discrete population of axons within a peripheral nerve fascicle. Some applications require, or would benefit greatly from, technology that could provide access to multiple discrete sites in several fascicles. The distributed intrafascicular multi-electrode (DIME) lead was developed to deploy multiple LIFEs to several fascicles. It consists of several (e.g. six) LIFEs that are coiled and placed in a sheath for strength and durability, with a portion left uncoiled to allow insertion at distinct sites. We have also developed a multi-lead multi-electrode (MLME) management system that includes a set of sheaths and procedures for fabrication and deployment. A prototype with 3 DIME leads was fabricated and tested in a procedure in a cadaver arm. The leads were successfully routed through skin and connective tissue and the deployment procedures were utilized to insert the LIFEs into fascicles of two nerves. Most multi-electrode systems use a single-lead, multi-electrode design. For some applications, this design may be limited by the bulk of the multi-contact array and/or by the spatial distribution of the electrodes. We have designed a system that can be used to access multiple sets of discrete groups of fibers that are spatially distributed in one or more fascicles of peripheral nerves. This system may be useful for neural-enabled prostheses or other applications. Copyright © 2014 Elsevier B.V. All rights reserved.

  15. Delaying the onset of treadmill exercise following peripheral nerve injury has different effects on axon regeneration and motoneuron synaptic plasticity.

    PubMed

    Brandt, Jaclyn; Evans, Jonathan T; Mildenhall, Taylor; Mulligan, Amanda; Konieczny, Aimee; Rose, Samuel J; English, Arthur W

    2015-04-01

    Transection of a peripheral nerve results in withdrawal of synapses from motoneurons. Some of the withdrawn synapses are restored spontaneously, but those containing the vesicular glutamate transporter 1 (VGLUT1), and arising mainly from primary afferent neurons, are withdrawn permanently. If animals are exercised immediately after nerve injury, regeneration of the damaged axons is enhanced and no withdrawal of synapses from injured motoneurons can be detected. We investigated whether delaying the onset of exercise until after synapse withdrawal had occurred would yield similar results. In Lewis rats, the right sciatic nerve was cut and repaired. Reinnervation of the soleus muscle was monitored until a direct muscle (M) response was observed to stimulation of the tibial nerve. At that time, rats began 2 wk of daily treadmill exercise using an interval training protocol. Both M responses and electrically-evoked H reflexes were monitored weekly for an additional seven wk. Contacts made by structures containing VGLUT1 or glutamic acid decarboxylase (GAD67) with motoneurons were studied from confocal images of retrogradely labeled cells. Timing of full muscle reinnervation was similar in both delayed and immediately exercised rats. H reflex amplitude in delayed exercised rats was only half that found in immediately exercised animals. Unlike immediately exercised animals, motoneuron contacts containing VGLUT1 in delayed exercised rats were reduced significantly, relative to intact rats. The therapeutic window for application of exercise as a treatment to promote restoration of synaptic inputs onto motoneurons following peripheral nerve injury is different from that for promoting axon regeneration in the periphery. Copyright © 2015 the American Physiological Society.

  16. A system and method to interface with multiple groups of axons in several fascicles of peripheral nerves

    PubMed Central

    Thota, Anil K.; Kuntaegowdanahalli, Sathyakumar; Starosciak, Amy K.; Abbas, James J.; Orbay, Jorge; Horch, Kenneth W.; Jung, Ranu

    2014-01-01

    Background Several neural interface technologies that stimulate and/or record from groups of axons have been developed. The longitudinal intrafascicular electrode (LIFE) is a fine wire that can provide access to a discrete population of axons within a peripheral nerve fascicle. Some applications require, or would benefit greatly from, technology that could provide access to multiple discrete sites in several fascicles. New Method The distributed intrafascicular multi-electrode (DIME) lead was developed to deploy multiple LIFEs to several fascicles. It consists of several (e.g. six) LIFEs that are coiled and placed in a sheath for strength and durability, with a portion left uncoiled to allow insertion at distinct sites. We have also developed a multi-lead multi-electrode (MLME) management system that includes a set of sheaths and procedures for fabrication and deployment. Results A prototype with 3 DIME leads was fabricated and tested in a procedure in a cadaver arm. The leads were successfully routed through skin and connective tissue and the deployment procedures were utilized to insert the LIFEs into fascicles of two nerves. Comparison with Existing Method(s) Most multi-electrode systems use a single-lead, multi-electrode design. For some applications, this design may be limited by the bulk of the multi-contact array and/or by the spatial distribution of the electrodes. Conclusion We have designed a system that can be used to access multiple sets of discrete groups of fibers that are spatially distributed in one or more fascicles of peripheral nerves. This system may be useful for neural-enabled prostheses or other applications. PMID:25092497

  17. Astrocytes Block Axonal Regeneration in Mammals by Activating the Physiological Stop Pathway

    NASA Astrophysics Data System (ADS)

    Liuzzi, Francis J.; Lasek, Raymond J.

    1987-08-01

    Regenerating sensory axons in the dorsal roots of adult mammals are stopped at the junction between the root and spinal cord by reactive astrocytes. Do these cells stop axonal elongation by activating the physiological mechanisms that normally operate to stop axons during development, or do they physically obstruct the elongating axons? In order to distinguish these possibilities, the cytology of the axon tips of regenerating axons that were stopped by astrocytes was compared with the axon tips that were physically obstructed at a cul-de-sac produced by ligating a peripheral nerve. The terminals of the physically obstructed axon tips were distended with neurofilaments and other axonally transported structures that had accumulated when the axons stopped elongating. By contrast, neurofilaments did not accumulate in the tips of regenerating axons that were stopped by spinal cord astrocytes at the dorsal root transitional zone. These axo-glial terminals resembled the terminals that axons make on target neurons during normal development. On the basis of these observations, astrocytes appear to stop axons from regenerating in the mammalian spinal cord by activating the physiological stop pathway that is built into the axon and that normally operates when axons form stable terminals on target cells.

  18. Motor evoked potentials enable differentiation between motor and sensory branches of peripheral nerves in animal experiments.

    PubMed

    Turkof, Edvin; Jurasch, Nikita; Knolle, Erik; Schwendenwein, Ilse; Habib, Danja; Unger, Ewald; Reichel, Martin; Losert, Udo

    2006-10-01

    Differentiation between motor and sensory fascicles is frequently necessary in reconstructive peripheral nerve surgery. The goal of this experimental study was to verify if centrally motor evoked potentials (MEP) could be implemented to differentiate sensory from motor fascicles, despite the well-known intermingling between nerve fascicles along their course to their distant periphery. This new procedure would enable surgeons to use MEP for placing nerve grafts at corresponding fascicles in the proximal and distal stumps without the need to use time-consuming staining. In ten sheep, both ulnar nerves were exposed at the terminal bifurcation between the last sensory and motor branch. Animals were then relaxed to avoid volume conduction. On central stimulation, the evoked nerve compound action potentials were simultaneously recorded from both terminal branches. In all cases, neurogenic motor nerve action potentials were recorded only from the terminal motor branch. The conclusion was that MEPs can be used for intraoperative differentiation between sensory and motor nerves. Further studies are necessary to develop this method for in situ measurements on intact nerve trunks.

  19. Differences in peripheral sensory input to the olfactory bulb between male and female mice

    NASA Astrophysics Data System (ADS)

    Kass, Marley D.; Czarnecki, Lindsey A.; Moberly, Andrew H.; McGann, John P.

    2017-04-01

    Female mammals generally have a superior sense of smell than males, but the biological basis of this difference is unknown. Here, we demonstrate sexually dimorphic neural coding of odorants by olfactory sensory neurons (OSNs), primary sensory neurons that physically contact odor molecules in the nose and provide the initial sensory input to the brain’s olfactory bulb. We performed in vivo optical neurophysiology to visualize odorant-evoked OSN synaptic output into olfactory bub glomeruli in unmanipulated (gonad-intact) adult mice from both sexes, and found that in females odorant presentation evoked more rapid OSN signaling over a broader range of OSNs than in males. These spatiotemporal differences enhanced the contrast between the neural representations of chemically related odorants in females compared to males during stimulus presentation. Removing circulating sex hormones makes these signals slower and less discriminable in females, while in males they become faster and more discriminable, suggesting opposite roles for gonadal hormones in influencing male and female olfactory function. These results demonstrate that the famous sex difference in olfactory abilities likely originates in the primary sensory neurons, and suggest that hormonal modulation of the peripheral olfactory system could underlie differences in how males and females experience the olfactory world.

  20. Changes induced by peripheral nerve injury in the morphology and nanomechanics of sensory neurons

    NASA Astrophysics Data System (ADS)

    Benzina, Ouafa; Szabo, Vivien; Lucas, Olivier; Saab, Marie-belle; Cloitre, Thierry; Scamps, Frédérique; Gergely, Csilla; Martin, Marta

    2013-06-01

    Peripheral nerve injury in vivo promotes a regenerative growth in vitro characterized by an improved neurite regrowth. Knowledge of the conditioning injury effects on both morphology and mechanical properties of live sensory neurons could be instrumental to understand the cellular and molecular mechanisms leading to this regenerative growth. In the present study, we use differential interference contrast microscopy, fluorescence microscopy and atomic force microscopy (AFM) to show that conditioned axotomy, induced by sciatic nerve injury, does not increase somatic size of sensory neurons from adult mice lumbar dorsal root ganglia but promotes the appearance of longer and larger neurites and growth cones. AFM on live neurons is also employed to investigate changes in morphology and membrane mechanical properties of somas of conditioned neurons following sciatic nerve injury. Mechanical analysis of the soma allows distinguishing neurons having a regenerative growth from control ones, although they show similar shapes and sizes.

  1. Mass Spectrometry Imaging and GC-MS Profiling of the Mammalian Peripheral Sensory-Motor Circuit

    NASA Astrophysics Data System (ADS)

    Rubakhin, Stanislav S.; Ulanov, Alexander; Sweedler, Jonathan V.

    2015-06-01

    Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) has evolved to become an effective discovery tool in science and clinical diagnostics. Here, chemical imaging approaches are applied to well-defined regions of the mammalian peripheral sensory-motor system, including the dorsal root ganglia (DRG) and adjacent nerves. By combining several MSI approaches, analyte coverage is increased and 195 distinct molecular features are observed. Principal component analysis suggests three chemically different regions within the sensory-motor system, with the DRG and adjacent nerve regions being the most distinct. Investigation of these regions using gas chromatography-mass spectrometry corroborate these findings and reveal important metabolic markers related to the observed differences. The heterogeneity of the structurally, physiologically, and functionally connected regions demonstrates the intricate chemical and spatial regulation of their chemical composition.

  2. Effect of helium-neon laser irradiation on peripheral sensory nerve latency

    SciTech Connect

    Snyder-Mackler, L.; Bork, C.E.

    1988-02-01

    The purpose of this randomized, double-blind study was to determine the effect of a helium-neon (He-Ne) laser on latency of peripheral sensory nerve. Forty healthy subjects with no history of right upper extremity pathological conditions were assigned to either a Laser or a Placebo Group. Six 1-cm2 blocks along a 12-cm segment of the subjects' right superficial radial nerve received 20-second applications of either the He-Ne laser or a placebo. We assessed differences between pretest and posttest latencies with t tests for correlated and independent samples. The Laser Group showed a statistically significant increase in latency that corresponded to a decrease in sensory nerve conduction velocity. Short-duration He-Ne laser application significantly increased the distal latency of the superficial radial nerve. This finding provides information about the mechanism of the reported pain-relieving effect of the He-Ne laser.

  3. Molecular signaling mechanisms of axon-glia communication in the peripheral nervous system.

    PubMed

    Grigoryan, Tamara; Birchmeier, Walter

    2015-05-01

    In this article we discuss the molecular signaling mechanisms that coordinate interactions between Schwann cells and the neurons of the peripheral nervous system. Such interactions take place perpetually during development and in adulthood, and are critical for the homeostasis of the peripheral nervous system (PNS). Neurons provide essential signals to control Schwann cell functions, whereas Schwann cells promote neuronal survival and allow efficient transduction of action potentials. Deregulation of neuron-Schwann cell interactions often results in developmental abnormalities and diseases. Recent investigations have shown that during development, neuronally provided signals, such as Neuregulin, Jagged, and Wnt interact to fine-tune the Schwann cell lineage progression. In adult, the signal exchange between neurons and Schwann cells ensures proper nerve function and regeneration. Identification of the mechanisms of neuron-Schwann cell interactions is therefore essential for our understanding of the development, function and pathology of the peripheral nervous system as a whole.

  4. Role of voltage-gated cation channels and axon reflexes in the release of sensory neuropeptides by capsaicin from isolated rat trachea.

    PubMed

    Németh, József; Helyes, Zsuzsanna; Oroszi, Gábor; Jakab, Balázs; Pintér, Erika; Szilvássy, Zoltán; Szolcsányi, János

    2003-01-05

    In order to reveal the role of axon reflexes and sensory receptors in sensory neuropeptide release in response to capsaicin, liberation of substance P, calcitonin gene-related peptide and somatostatin from isolated rat tracheae was investigated in the presence of voltage-sensitive Na(+) and Ca(2+) channel blocking agents. Neuropeptide release induced by capsaicin (10 nM) remained unchanged in the presence of 25 mM lidocaine, 1 microM tetrodotoxin or the N-type Ca(2+) channel inhibitor, omega-conotoxin GVIA (100-300 nM). Peptide release by 100 pulses of 2 Hz field stimulation was prevented by lidocaine or tetrodotoxin. Omega-agatoxin TK (250 nM) significantly inhibited and Cd(2+) (200 microM) prevented capsaicin-induced neuropeptide release. These results suggest that chemical stimulation-induced neuropeptide release does not involve activation of fast Na(+) channels or N- and P-type voltage-dependent Ca(2+) channels, but contribution of Q-type Ca(2+) channels is possible. Sensory neuropeptides are released by capsaicin from sensory receptors without axon reflexes.

  5. Identification of a signaling cascade that maintains constitutive delta opioid receptor incompetence in peripheral sensory neurons.

    PubMed

    Brackley, Allison Doyle; Sarrami, Shayda; Gomez, Ruben; Guerrero, Kristi A; Jeske, Nathaniel A

    2017-04-05

    Mu opioid receptor (MOR) agonists are often used to treat severe pain, but can result in adverse side effects. To circumvent systemic side effects, targeting peripheral opioid receptors is an attractive alternative treatment for severe pain. Activation of the delta opioid receptor (DOR) produces similar analgesia with reduced side effects. However, until primed by inflammation, peripheral DOR is analgesically incompetent, raising interest in the mechanism. We recently identified a novel role for G protein-coupled receptor kinase 2 (GRK2) that renders DOR analgesically incompetent at the plasma membrane. However, the mechanism that maintains constitutive GRK2 association with DOR is unknown. Protein kinase A (PKA) phosphorylation of GRK2 at Ser685 targets it to the plasma membrane. A-kinase anchoring protein 79/150 (AKAP), residing at the plasma membrane in neurons, scaffolds PKA to target proteins to mediate downstream signal. Therefore, we sought to determine whether GRK2-mediated DOR desensitization is directed by PKA via AKAP scaffolding. Membrane fractions from cultured rat sensory neurons following AKAP siRNA-transfection and from AKAP-knockout mice, had less PKA activity, GRK2 Ser685 phosphorylation, and GRK2 plasma membrane targeting than controls. Site-directed mutagenesis revealed that GRK2 Ser685 phosphorylation drives GRK2s association with plasma membrane-associated DOR. Moreover, overexpression studies with AKAP mutants indicated that impaired AKAP-mediated PKA scaffolding significantly reduces DOR-GRK2 association at the plasma membrane and consequently increases DOR activity in sensory neurons without a priming event. These findings suggest that AKAP scaffolds PKA to increase plasma membrane targeting and phosphorylation of GRK2 to maintain DOR analgesic incompetence in peripheral sensory neurons.

  6. Burning pain: axonal dysfunction in erythromelalgia.

    PubMed

    Farrar, Michelle A; Lee, Ming-Jen; Howells, James; Andrews, Peter I; Lin, Cindy S-Y

    2017-05-01

    Erythromelalgia (EM) is a rare neurovascular disorder characterized by intermittent severe burning pain, erythema, and warmth in the extremities on heat stimuli. To investigate the underlying pathophysiology, peripheral axonal excitability studies were performed and changes with heating and therapy explored. Multiple excitability indices (stimulus-response curve, strength-duration time constant (SDTC), threshold electrotonus, and recovery cycle) were investigated in 23 (9 EMSCN9A+ and 14 EMSCN9A-) genetically characterized patients with EM stimulating median motor and sensory axons at the wrist. At rest, patients with EM showed a higher threshold and rheobase (P < 0.001) compared with controls. Threshold electrotonus and current-voltage relationships demonstrated greater changes of thresholds in both depolarizing and hyperpolarizing preconditioning electrotonus in both EM cohorts compared with controls in sensory axons (P < 0.005). When average temperature was raised from 31.5°C to 36.3°C in EMSCN9A+ patients, excitability changes showed depolarization, specifically SDTC significantly increased, in contrast to the effects of temperature previously established in healthy subjects (P < 0.05). With treatment, 4 EMSCN9A+ patients (4/9) reported improvement with mexiletine, associated with reduction in SDTC in motor and sensory axons. This is the first study of primary EM using threshold tracking techniques to demonstrate alterations in peripheral axonal membrane function. Taken together, these changes may be attributed to systemic neurovascular abnormalities in EM, with chronic postischaemic resting membrane potential hyperpolarization due to Na/K pump overactivity. With heating, a trigger of acute symptoms, axonal depolarization developed, corresponding to acute axonal ischaemia. This study has provided novel insights into EM pathophysiology.

  7. Burning pain: axonal dysfunction in erythromelalgia

    PubMed Central

    Farrar, Michelle A.; Lee, Ming-Jen; Howells, James; Andrews, Peter I.; Lin, Cindy S.-Y.

    2017-01-01

    Abstract Erythromelalgia (EM) is a rare neurovascular disorder characterized by intermittent severe burning pain, erythema, and warmth in the extremities on heat stimuli. To investigate the underlying pathophysiology, peripheral axonal excitability studies were performed and changes with heating and therapy explored. Multiple excitability indices (stimulus–response curve, strength–duration time constant (SDTC), threshold electrotonus, and recovery cycle) were investigated in 23 (9 EMSCN9A+ and 14 EMSCN9A−) genetically characterized patients with EM stimulating median motor and sensory axons at the wrist. At rest, patients with EM showed a higher threshold and rheobase (P < 0.001) compared with controls. Threshold electrotonus and current–voltage relationships demonstrated greater changes of thresholds in both depolarizing and hyperpolarizing preconditioning electrotonus in both EM cohorts compared with controls in sensory axons (P < 0.005). When average temperature was raised from 31.5°C to 36.3°C in EMSCN9A+ patients, excitability changes showed depolarization, specifically SDTC significantly increased, in contrast to the effects of temperature previously established in healthy subjects (P < 0.05). With treatment, 4 EMSCN9A+ patients (4/9) reported improvement with mexiletine, associated with reduction in SDTC in motor and sensory axons. This is the first study of primary EM using threshold tracking techniques to demonstrate alterations in peripheral axonal membrane function. Taken together, these changes may be attributed to systemic neurovascular abnormalities in EM, with chronic postischaemic resting membrane potential hyperpolarization due to Na+/K+ pump overactivity. With heating, a trigger of acute symptoms, axonal depolarization developed, corresponding to acute axonal ischaemia. This study has provided novel insights into EM pathophysiology. PMID:28134657

  8. A critical appraisal of the mild axonal peripheral neuropathy of late neurologic Lyme disease.

    PubMed

    Wormser, Gary P; Strle, Franc; Shapiro, Eugene D; Dattwyler, Raymond J; Auwaerter, Paul G

    2017-02-01

    In older studies, a chronic distal symmetric sensory neuropathy was reported as a relatively common manifestation of late Lyme disease in the United States. However, the original papers describing this entity had notable inconsistencies and certain inexplicable findings, such as reports that this condition developed in patients despite prior antibiotic treatment known to be highly effective for other manifestations of Lyme disease. More recent literature suggests that this entity is seen rarely, if at all. A chronic distal symmetric sensory neuropathy as a manifestation of late Lyme disease in North America should be regarded as controversial and in need of rigorous validation studies before acceptance as a documented clinical entity. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Acute motor and sensory axonal neuropathy (AMSAN) in a 15-year-old boy presenting with severe pain and distal muscle weakness.

    PubMed

    Rostásy, K M; Huppke, P; Beckers, B; Brockmann, K; Degenhardt, V; Wesche, B; König, F; Gärtner, J

    2005-08-01

    Acute motor and sensory axonal neuropathy (AMSAN) is a recently described subtype of Guillain-Barré syndrome characterized by acute onset of distal weakness, loss of deep tendon reflexes and sensory symptoms. Electrophysiological studies show mildly reduced nerve conduction velocities combined with a marked reduction of muscle action and sensory nerve action potentials. Here, we report a 15-year-old boy who suffered from severe burning and knife-like pain that increased over a period of three months and resulted in a disrupted sleep pattern and suicidal intentions as well as marked loss of weight. In addition, he developed muscle weakness in his hands and feet. Neurophysiological and histopathological studies revealed AMSAN. Marked improvement of his condition was achieved by treatment with intravenous immunoglobulins, high-dose methylprednisolone, and a combination of gabapentin, antidepressants, and an oral morphine.

  10. Relationship between vitamin B12 and sensory and motor peripheral nerve function in older adults.

    PubMed

    Leishear, Kira; Boudreau, Robert M; Studenski, Stephanie A; Ferrucci, Luigi; Rosano, Caterina; de Rekeneire, Nathalie; Houston, Denise K; Kritchevsky, Stephen B; Schwartz, Ann V; Vinik, Aaron I; Hogervorst, Eva; Yaffe, Kristine; Harris, Tamara B; Newman, Anne B; Strotmeyer, Elsa S

    2012-06-01

    To examine whether deficient B12 status or low serum B12 levels are associated with worse sensory and motor peripheral nerve function in older adults. Cross-sectional. Health, Aging and Body Composition Study. Two thousand two hundred and eighty-seven adults aged 72 to 83 (mean 76.5 ± 2.9; 51.4% female; 38.3% black). Low serum B12 was defined as serum B12 less than 260 pmol/L, and deficient B12 status was defined as B12 less than 260 pmol/L, methylmalonic acid (MMA) greater than 271 nmol/L, and MMA greater than 2-methylcitrate. Peripheral nerve function was assessed according to peroneal nerve conduction amplitude and velocity (NCV) (motor), 1.4 g/10 g monofilament detection, average vibration threshold detection, and peripheral neuropathy symptoms (numbness, aching or burning pain, or both) (sensory). B12-deficient status was found in 7.0% of participants, and an additional 10.1% had low serum B12 levels. B12 deficient status was associated with greater insensitivity to light (1.4 g) touch (odds ratio = 1.50, 95% confidence interval = 1.06-2.13) and worse NCV (42.3 vs 43.5 m/s) (β = -1.16, P = .01) after multivariable adjustment for demographics, lifestyle factors, and health conditions. Associations were consistent for the alternative definition using low serum B12 only. No significant associations were found for deficient B12 status or the alternative low serum B12 definition and vibration detection, nerve conduction amplitude, or peripheral neuropathy symptoms. Poor B12 (deficient B12 status and low serum B12) is associated with worse sensory and motor peripheral nerve function. Nerve function impairments may lead to physical function declines and disability in older adults, suggesting that prevention and treatment of low B12 levels may be important to evaluate. © 2012, Copyright the Authors Journal compilation © 2012, The American Geriatrics Society.

  11. Peptidomics and Secretomics of the Mammalian Peripheral Sensory-Motor System

    NASA Astrophysics Data System (ADS)

    Tillmaand, Emily G.; Yang, Ning; Kindt, Callie A. C.; Romanova, Elena V.; Rubakhin, Stanislav S.; Sweedler, Jonathan V.

    2015-12-01

    The dorsal root ganglion (DRG) and its anatomically and functionally associated spinal nerve and ventral and dorsal roots are important components of the peripheral sensory-motor system in mammals. The cells within these structures use a number of peptides as intercellular signaling molecules. We performed a variety of mass spectrometry (MS)-based characterizations of peptides contained within and secreted from these structures, and from isolated and cultured DRG cells. Liquid chromatography-Fourier transform MS was utilized in DRG and nerve peptidome analysis. In total, 2724 peptides from 296 proteins were identified in tissue extracts. Neuropeptides are among those detected, including calcitonin gene-related peptide I, little SAAS, and known hemoglobin-derived peptides. Solid phase extraction combined with direct matrix-assisted laser desorption/ionization time-of-flight MS was employed to investigate the secretome of these structures. A number of peptides were detected in the releasate from semi-intact preparations of DRGs and associated nerves, including neurofilament- and myelin basic protein-related peptides. A smaller set of analytes was observed in releasates from cultured DRG neurons. The peptide signals observed in the releasates have been mass-matched to those characterized and identified in homogenates of entire DRGs and associated nerves. This data aids our understanding of the chemical composition of the mammalian peripheral sensory-motor system, which is involved in key physiological functions such as nociception, thermoreception, itch sensation, and proprioception.

  12. Recording sensory and motor information from peripheral nerves with Utah Slanted Electrode Arrays.

    PubMed

    Clark, Gregory A; Ledbetter, Noah M; Warren, David J; Harrison, Reid R

    2011-01-01

    Recording and stimulation via high-count penetrating microelectrode arrays implanted in peripheral nerves may help restore precise motor and sensory function after nervous system damage or disease. Although previous work has demonstrated safety and relatively successful stimulation for long-term implants of 100-electrode Utah Slanted Electrode Arrays (USEAs) in feline sciatic nerve [1], two major remaining challenges were 1) to maintain viable recordings of nerve action potentials long-term, and 2) to overcome contamination of unit recordings by myoelectric (EMG) activity in awake, moving animals. In conjunction with improvements to USEAs themselves, we have redesigned several aspects of our USEA containment and connector systems. Although further increases in unit yield and long-term stability remain desirable, here we report considerable progress toward meeting both of these goals: We have successfully recorded unit activity from USEAs implanted intrafascicularly in sciatic nerve for periods up to 4 months (the terminal experimental time point), and we have developed a containment system that effectively eliminates or substantially reduces EMG contamination of unit recordings in the moving animal. In addition, we used a 100-channel wireless recording integrated circuit attached to implanted USEAs to transmit broadband or spike-threshold data from nerve. Neural data thusly obtained during imposed limb movements were decoded blindly to drive a virtual prosthetic limb in real time. These results support the possibility of using USEAs in peripheral nerves to provide motor control and cutaneous or proprioceptive sensory feedback in individuals after limb loss or spinal cord injury.

  13. Morphology, innervation, and peripheral sensory cells of the siphon of aplysia californica.

    PubMed

    Carrigan, Ian D; Croll, Roger P; Wyeth, Russell C

    2015-11-01

    The siphon of Aplysia californica has several functions, including involvement in respiration, excretion, and defensive inking. It also provides sensory input for defensive withdrawals that have been studied extensively to examine mechanisms that underlie learning. To better understand the neuronal bases of these functions, we used immunohistochemistry to catalogue peripheral cell types and innervation of the siphon in stage 12 juveniles (chosen to allow observation of tissues in whole-mounts). We found that the siphon nerve splits into three major branches, leading ultimately to a two-part FMRFamide-immunoreactive plexus and an apparently separate tyrosine hydroxylase-immunoreactive plexus. Putative sensory neurons included four distinct types of tubulin-immunoreactive bipolar cells (one likely also tyrosine hydroxylase immunoreactive) that bore ciliated dendrites penetrating the epithelium. A fifth bipolar neuron type (tubulin- and FMRFamide-immunoreactive) occurred deeper in the tissue, associated with part of the FMRFamide-immunoreactive plexus. Our observations emphasize the structural complexity of the peripheral nervous system of the siphon, and the importance of direct tests of the various components to better understand the functioning of the entire organ, including its role in defensive withdrawal responses. © 2015 Wiley Periodicals, Inc.

  14. Late form of Pompe disease with glycogen storage in peripheral nerves axons.

    PubMed

    Fidziańska, Anna; Ługowska, Agnieszka; Tylki-Szymańska, Anna

    2011-02-15

    Pompe disease is caused by the deficiency of acid α-glucosidase (GAA), which degrades glycogen into glucose. Its manifestation is characterized by a broad and continuous spectrum of clinical severity ranging from severe infantile to relatively benign adult form. We describe a 12-year-old girl diagnosed at a presymptomatic stage of late form Pompe disease due to fortuitous detection of an elevated level of serum creatine kinase (CK) at the age of 4. Biopsies were taken from the quadriceps muscle and studied with histological and histochemical techniques, as well as in electron microscope. Sporadic muscle cells showed the accumulation of lysosomal glycogen, suggesting Pompe disease. Interestingly, we found lysosomal bound glycogen, located in the axons of intramuscular nerves. The diagnosis was confirmed by deficient GAA activity in leukocytes. Mutation analysis revealed changes IVS1-13T>G and p.C103G in the GAA gene. The patient was able to obtain enzyme replacement therapy in the early asymptomatic stage of the disease.

  15. Amplitude of sensory nerve action potential in early stage diabetic peripheral neuropathy: an analysis of 500 cases

    PubMed Central

    Zhang, Yunqian; Li, Jintao; Wang, Tingjuan; Wang, Jianlin

    2014-01-01

    Early diagnosis of diabetic peripheral neuropathy is important for the successful treatment of diabetes mellitus. In the present study, we recruited 500 diabetic patients from the Fourth Affiliated Hospital of Kunming Medical University in China from June 2008 to September 2013: 221 cases showed symptoms of peripheral neuropathy (symptomatic group) and 279 cases had no symptoms of peripheral impairment (asymptomatic group). One hundred healthy control subjects were also recruited. Nerve conduction studies revealed that distal motor latency was longer, sensory nerve conduction velocity was slower, and sensory nerve action potential and amplitude of compound muscle action potential were significantly lower in the median, ulnar, posterior tibial and common peroneal nerve in the diabetic groups compared with control subjects. Moreover, the alterations were more obvious in patients with symptoms of peripheral neuropathy. Of the 500 diabetic patients, neural conduction abnormalities were detected in 358 cases (71.6%), among which impairment of the common peroneal nerve was most prominent. Sensory nerve abnormality was more obvious than motor nerve abnormality in the diabetic groups. The amplitude of sensory nerve action potential was the most sensitive measure of peripheral neuropathy. Our results reveal that varying degrees of nerve conduction changes are present in the early, asymptomatic stage of diabetic peripheral neuropathy. PMID:25221597

  16. Amplitude of sensory nerve action potential in early stage diabetic peripheral neuropathy: an analysis of 500 cases.

    PubMed

    Zhang, Yunqian; Li, Jintao; Wang, Tingjuan; Wang, Jianlin

    2014-07-15

    Early diagnosis of diabetic peripheral neuropathy is important for the successful treatment of diabetes mellitus. In the present study, we recruited 500 diabetic patients from the Fourth Affiliated Hospital of Kunming Medical University in China from June 2008 to September 2013: 221 cases showed symptoms of peripheral neuropathy (symptomatic group) and 279 cases had no symptoms of peripheral impairment (asymptomatic group). One hundred healthy control subjects were also recruited. Nerve conduction studies revealed that distal motor latency was longer, sensory nerve conduction velocity was slower, and sensory nerve action potential and amplitude of compound muscle action potential were significantly lower in the median, ulnar, posterior tibial and common peroneal nerve in the diabetic groups compared with control subjects. Moreover, the alterations were more obvious in patients with symptoms of peripheral neuropathy. Of the 500 diabetic patients, neural conduction abnormalities were detected in 358 cases (71.6%), among which impairment of the common peroneal nerve was most prominent. Sensory nerve abnormality was more obvious than motor nerve abnormality in the diabetic groups. The amplitude of sensory nerve action potential was the most sensitive measure of peripheral neuropathy. Our results reveal that varying degrees of nerve conduction changes are present in the early, asymptomatic stage of diabetic peripheral neuropathy.

  17. Factors predicting sensory and motor recovery after the repair of upper limb peripheral nerve injuries

    PubMed Central

    He, Bo; Zhu, Zhaowei; Zhu, Qingtang; Zhou, Xiang; Zheng, Canbin; Li, Pengliang; Zhu, Shuang; Liu, Xiaolin; Zhu, Jiakai

    2014-01-01

    OBJECTIVE: To investigate the factors associated with sensory and motor recovery after the repair of upper limb peripheral nerve injuries. DATA SOURCES: The online PubMed database was searched for English articles describing outcomes after the repair of median, ulnar, radial, and digital nerve injuries in humans with a publication date between 1 January 1990 and 16 February 2011. STUDY SELECTION: The following types of article were selected: (1) clinical trials describing the repair of median, ulnar, radial, and digital nerve injuries published in English; and (2) studies that reported sufficient patient information, including age, mechanism of injury, nerve injured, injury location, defect length, repair time, repair method, and repair materials. SPSS 13.0 software was used to perform univariate and multivariate logistic regression analyses and to investigate the patient and intervention factors associated with outcomes. MAIN OUTCOME MEASURES: Sensory function was assessed using the Mackinnon-Dellon scale and motor function was assessed using the manual muscle test. Satisfactory motor recovery was defined as grade M4 or M5, and satisfactory sensory recovery was defined as grade S3+ or S4. RESULTS: Seventy-one articles were included in this study. Univariate and multivariate logistic regression analyses showed that repair time, repair materials, and nerve injured were independent predictors of outcome after the repair of nerve injuries (P < 0.05), and that the nerve injured was the main factor affecting the rate of good to excellent recovery. CONCLUSION: Predictors of outcome after the repair of peripheral nerve injuries include age, gender, repair time, repair materials, nerve injured, defect length, and duration of follow-up. PMID:25206870

  18. Substance P-immunoreactive peripheral branches of sensory neurons innervate guinea pig sympathetic neurons

    PubMed Central

    Matthews, Margaret R.; Cuello, A. Claudio

    1982-01-01

    The presence of substance P-immunoreactive (SPI) varicose nerve networks and nerve fiber bundles in guinea pig prevertebral sympathetic ganglia has been confirmed by fluorescence immunohistochemistry. No SPI neurons have been found in sympathetic ganglia, including lumbar paravertebral ganglia. Peroxidase-antiperoxidase immunocytochemical methods have shown that SPI nerve terminal varicosities in the inferior mesenteric ganglion (IMG) form morphologically identifiable synapses on dendritic shafts. Cutting the intermesenteric nerve produces no obvious change in SP immunoreactivity in the IMG; cutting the lumbar splanchnic nerves produces nearly total depletion which becomes virtually complete if the two lesions are combined; SP immunoreactivity accumulates in the central ends of the lumbar splanchnic nerves and in the cranial end of the intermesenteric nerve. Cutting hypogastric nerves or colonic branches of the IMG leads to accumulation of SP immunoreactivity in their ganglionic stumps and to build-up (colonic nerve lesion) rather than depletion of SP immunoreactivity in the IMG. Capsaicin treatment leads to total loss of SP immunoreactivity from the prevertebral ganglia and dorsal root ganglia, severe depletion in laminae I and II and dorsolateral fasciculus of the spinal cord, and total loss from perivascular and paravascular networks of the ileum and mesentery, with sparing of the SP immunoreactivity of the enteric nerve plexuses. Capsaicin is thought to deplete sensory neurons selectively. Removal of the spinal cord below T7 without damage to the dorsal root ganglia leaves the intraganglionic SPI nerve networks and bundles intact. We conclude that these are derived from peripheral processes of sensory neurons and we propose that the SPI synapses in the IMG arise from collateral branches of these sensory peripheral processes. This implies a novel role for these processes, in forming intraganglionically in the prevertebral ganglia synapses which may take part in

  19. Relation of Sensory Peripheral Neuropathy in Sjögren Syndrome to anti-Ro/SSA

    PubMed Central

    Scofield, Amanda K.; Radfar, Lida; Ice, John; Vista, Evan; Anaya, Juan-Manuel; Houston, Glen; Lewis, David; Stone, Donald U.; Chodosh, James; Hefner, Kimberly; Lessard, Christopher J.; Moser, Kathy L.; Scofield, R. Hal

    2013-01-01

    Background Sjögren syndrome is a common, chronic autoimmune disease that typically produces inflammation and poor function of the salivary and lacrimal glands. Other organs can be affected, including the nervous system. Sensory peripheral neuropathy is a common manifestation of the disease. Methods Eight-eight patients attending a dry eyes-dry mouth clinic were classified as primary Sjögren syndrome and underwent a neurological examination. Anti-Ro (or SSA) and anti-La (or SSB) were determined using immunodiffusion as well as Inno-Lia and BioPlex ANA screen. Serum vitamin B12 levels were determined using an enzyme-linked microtiter plate assay. Results Twenty-seven (31%) of the 88 patients had peripheral neuropathy as defined by loss of light touch, proprioception or vibratory sensation. Anti-Ro and anti-La were found by immunodiffusion in 12 patients, and 8 of these 12 had neuropathy (χ2=8.46, p=0.0036, odds ratio = 6.0 compared to those without precipitating anti-Ro and anti-La). Of the 27 patients with only anti-Ro by immunodiffusion, 13 (48.1%) of these had neuropathy (χ2 =5.587, p=0.018 compared to those without anti-Ro). There was no relationship of the other, more sensitive measures of anti-Ro and anti-La to neuropathy. In addition, we found no association of serum vitamin B12 levels to neuropathy among these patients with Sjögren syndrome. Conclusion Sensory peripheral neuropathy is common among patients with Sjögren syndrome, and is associated with the presence of anti-Ro and anti-La when determined by immunodiffusion. PMID:22955477

  20. Sensory and cognitive influences on the training-related improvement of reading speed in peripheral vision

    PubMed Central

    He, Yingchen; Legge, Gordon E.; Yu, Deyue

    2013-01-01

    Reading speed in normal peripheral vision is slow but can be increased through training on a letter-recognition task. The aim of the present study is to investigate the sensory and cognitive factors responsible for this improvement. The visual span is hypothesized to be a sensory bottleneck limiting reading speed. Three sensory factors—letter acuity, crowding, and mislocations (errors in the spatial order of letters)—may limit the size of the visual span. Reading speed is also influenced by cognitive factors including the utilization of information from sentence context. We conducted a perceptual training experiment to investigate the roles of these factors. Training consisted of four daily sessions of trigram letter-recognition trials at 10° in the lower visual field. Subjects' visual-span profiles and reading speeds were measured in pre- and posttests. Effects of the three sensory factors were isolated through a decomposition analysis of the visual span profiles. The impact of sentence context was indexed by context gain, the ratio of reading speeds for ordered and unordered text. Following training, visual spans increased in size by 5.4 bits of information transmitted, and reading speeds increased by 45%. Training induced a substantial reduction in the magnitude of crowding (4.8 bits) and a smaller reduction for mislocations (0.7 bits), but no change in letter acuity or context gain. These results indicate that the basis of the training-related improvement in reading speed is a large reduction in the interfering effect of crowding and a small reduction of mislocation errors. PMID:23798030

  1. Trigeminal pain and quantitative sensory testing in painful peripheral diabetic neuropathy.

    PubMed

    Arap, Astrid; Siqueira, Silvia R D T; Silva, Claudomiro B; Teixeira, Manoel J; Siqueira, José T T

    2010-07-01

    To evaluate patients with Diabetes Mellitus type 2 and painful peripheral neuropathy in order to investigate oral complaints and facial somatosensory findings. Case-control study; 29 patients (12 women, mean age 57.86 yo) with Diabetes Mellitus type 2 and 31 age-gender-matched controls were evaluated with a standardized protocol for general characteristics, orofacial pain, research diagnostic criteria for temporomandibular disorders, visual analogue scale and McGill Pain questionnaire, and a systematic protocol of quantitative sensory testing for bilateral facial sensitivity at the areas innervated by the trigeminal branches, which included the thermal detection by ThermoSensi 2, tactile evaluation with vonFrey filaments, and superficial pain thresholds with a superficial algometer (Micromar). Statistical analysis was performed with Wilcoxon, chi-square, confidence intervals and Spearman (p<0.05). Orofacial pain was reported by 55.2% of patients, and the most common descriptor was fatigue (50%); 17.2% had burning mouth. Myofascial temporomandibular disorders were diagnosed in 9 (31%) patients. The study group showed higher sensory thresholds of pain at the right maxillary branch (p=0.017) but sensorial differences were not associated with pain (p=0.608). Glycemia and HbA(1c) were positively correlated with the quantitative sensory testing results of pain (p<0.05) and cold (p=0.044) perceptions. Higher pain thresholds were correlated with higher glycemia and glycated hemoglobin (p=0.027 and p=0.026). There was a high prevalence of orofacial pain and burning mouth was the most common complaint. The association of loss of pain sensation and higher glycemia and glycated hemoglobin can be of clinical use for the follow-up of DM complications. 2010 Elsevier Ltd. All rights reserved.

  2. Peripheral sensory activation of cortical circuits in the leg motor cortex of man

    PubMed Central

    Roy, François D; Gorassini, Monica A

    2008-01-01

    Peripheral sensory afferents in the hand activate both excitatory and inhibitory intracortical circuits to potentially facilitate and prune descending motor commands. In this study, we characterized how afferent inputs modulate the excitability of cortical circuits in the leg area of the primary motor cortex by examining how stimulation of the tibial nerve (TN) at the ankle alters motor evoked potentials (MEPs) activated by transcranial magnetic stimulation (TMS). Resting MEPs in the tibialis anterior (TA) muscle were facilitated in response to heteronymous activation of the TN 45–50 ms earlier, whereas MEPs were inhibited at interstimulus intervals of 32.5–37.5 ms. Similar time-dependent modulation occurred in the soleus (SOL) muscle with stimulation of the homonymous posterior tibial nerve (PTN) at the knee. To determine the site of this afferent-evoked facilitation and inhibition (spinal or cortical), we compared the effects of afferent stimulation to responses evoked at subcortical sites. At interstimulus intervals where MEP facilitation was observed (near 50 ms), spinal H-reflexes and responses evoked from corticospinal tract stimulation at the brainstem were predominantly depressed by the sensory stimulus suggesting that the observed MEP facilitation was cortical in origin. At interstimulus intervals where MEP depression was observed (near 35 ms), brainstem evoked responses were depressed to a similar degree and, in contrast to the hand, this suggests that spinal rather than cortical circuits mediate short-latency afferent inhibition (SAI) of leg MEPs. When the MEP was facilitated by afferent inputs, short-interval intracortical inhibition (SICI) was reduced and intracortical facilitation (ICF) was increased, but long-interval intracortical inhibition (LICI) at a 100 ms interval was unchanged. In addition, sensory excitation increased the recruitment of early, middle and late descending corticospinal volleys as evidenced from increases in MEP facilitation

  3. Quantitative Sensory Testing in Painful Hand Osteoarthritis Demonstrates Features of Peripheral Sensitisation

    PubMed Central

    Wajed, Julekha; Ejindu, Vivian; Heron, Christine; Hermansson, Monika; Kiely, Patrick; Sofat, Nidhi

    2012-01-01

    Hand osteoarthritis (HOA) is a prevalent condition for which treatments are based on analgesia and physical therapies. Our primary objective was to evaluate pain perception in participants with HOA by assessing the characteristics of nodal involvement, pain threshold in each hand joint, and radiological severity. We hypothesised that inflammation in hand osteoarthritis joints enhances sensitivity and firing of peripheral nociceptors, thereby causing chronic pain. Participants with proximal and distal interphalangeal (PIP and DIP) joint HOA and non-OA controls were recruited. Clinical parameters of joint involvement were measured including clinical nodes, VAS (visual analogue score) for pain (0–100 mm scale), HAQ (health assessment questionnaire), and Kellgren-Lawrence scores for radiological severity and pain threshold measurement were performed. The mean VAS in HOA participants was 59.3 mm ± 8.19 compared with 4.0 mm ± 1.89 in the control group (P < 0.0001). Quantitative sensory testing (QST) demonstrated lower pain thresholds in DIP/PIP joints and other subgroups in the OA group including the thumb, metacarpophalangeal (MCPs), joints, and wrists (P < 0.008) but not in controls (P = 0.348). Our data demonstrate that HOA subjects are sensitised to pain due to increased firing of peripheral nociceptors. Future work to evaluate mechanisms of peripheral sensitisation warrants further investigation. PMID:23209475

  4. A genome-wide association study identifies novel loci for paclitaxel-induced sensory peripheral neuropathy in CALGB 40101.

    PubMed

    Baldwin, R Michael; Owzar, Kouros; Zembutsu, Hitoshi; Chhibber, Aparna; Kubo, Michiaki; Jiang, Chen; Watson, Dorothy; Eclov, Rachel J; Mefford, Joel; McLeod, Howard L; Friedman, Paula N; Hudis, Clifford A; Winer, Eric P; Jorgenson, Eric M; Witte, John S; Shulman, Lawrence N; Nakamura, Yusuke; Ratain, Mark J; Kroetz, Deanna L

    2012-09-15

    Sensory peripheral neuropathy is a common and sometimes debilitating toxicity associated with paclitaxel therapy. This study aims to identify genetic risk factors for the development of this toxicity. A prospective pharmacogenetic analysis of patients with primary breast cancer, randomized to the paclitaxel arm of CALGB 40101, was used to identify genetic predictors of the onset and severity of sensory peripheral neuropathy. A genome-wide association study in 855 subjects of European ancestry was conducted and findings were replicated in additional European (n = 154) and African American (n = 117) subjects. A single nucleotide polymorphism in FGD4 was associated with the onset of sensory peripheral neuropathy in the discovery cohort [rs10771973; HR, 1.57; 95% confidence interval (CI), 1.30-1.91; P = 2.6 × 10(-6)] and in a European (HR, 1.72; 95% CI, 1.06-2.80; P = 0.013) and African American (HR, 1.93; 95% CI, 1.13-3.28; P = 6.7 × 10(-3)) replication cohort. There is also evidence that markers in additional genes, including EPHA5 (rs7349683) and FZD3 (rs10771973), were associated with the onset or severity of paclitaxel-induced sensory peripheral neuropathy. A genome-wide association study has identified novel genetic markers of paclitaxel-induced sensory peripheral neuropathy, including a common polymorphism in FGD4, a congenital peripheral neuropathy gene. These findings suggest that genetic variation may contribute to variation in development of this toxicity. Validation of these findings may allow for the identification of patients at increased risk of peripheral neuropathy and inform the use of an alternative to paclitaxel and/or the clinical management of this toxicity. ©2012 AACR.

  5. A Genome-Wide Association Study Identifies Novel Loci for Paclitaxel-Induced Sensory Peripheral Neuropathy in CALGB 40101

    PubMed Central

    Baldwin, R. Michael; Owzar, Kouros; Zembutsu, Hitoshi; Chhibber, Aparna; Kubo, Michiaki; Jiang, Chen; Watson, Dorothy; Eclov, Rachel J.; Mefford, Joel; McLeod, Howard L.; Friedman, Paula N.; Hudis, Clifford A.; Winer, Eric P.; Jorgenson, Eric M.; Witte, John S.; Shulman, Lawrence N.; Nakamura, Yusuke; Ratain, Mark J.; Kroetz, Deanna L.

    2012-01-01

    Purpose Sensory peripheral neuropathy is a common and sometimes debilitating toxicity associated with paclitaxel therapy. This study aims to identify genetic risk factors for development of this toxicity. Experimental Design A prospective pharmacogenetic analysis of primary breast cancer patients randomized to the paclitaxel arm of CALGB 40101 was used to identify genetic predictors of the onset and severity of sensory peripheral neuropathy. A genome-wide association study in 855 subjects of European ancestry was performed and findings were replicated in additional European (n = 154) and African American (n = 117) subjects. Results A single nucleotide polymorphism in FGD4 was associated with the onset of sensory peripheral neuropathy in the discovery cohort (rs10771973; HR, 1.57; 95% CI, 1.30–1.91; P = 2.6 × 10−6) and in a European (HR, 1.72; 95% CI, 1.06–2.80; P = 0.013) and African American (HR, 1.93; 95% CI, 1.13-3.28; P = 6.7 × 10−3) replication cohort. There is also evidence that markers in additional genes, including EPHA5 (rs7349683) and FZD3 (rs10771973), were associated with the onset or severity of paclitaxel-induced sensory peripheral neuropathy. Conclusions A genome-wide association study has identified novel genetic markers of paclitaxel-induced sensory peripheral neuropathy, including a common polymorphism in FGD4, a congenital peripheral neuropathy gene. These findings suggest that genetic variation may contribute to variation in development of this toxicity. Validation of these findings may allow for the identification of patients at increased risk of peripheral neuropathy and inform the use of an alternative to paclitaxel and/or the clinical management of this toxicity. PMID:22843789

  6. Loss of Peripheral Sensory Function Explains Much of the Increase in Postural Sway in Healthy Older Adults.

    PubMed

    Anson, Eric; Bigelow, Robin T; Swenor, Bonnielin; Deshpande, Nandini; Studenski, Stephanie; Jeka, John J; Agrawal, Yuri

    2017-01-01

    Postural sway increases with age and peripheral sensory disease. Whether, peripheral sensory function is related to postural sway independent of age in healthy adults is unclear. Here, we investigated the relationship between tests of visual function (VISFIELD), vestibular function (CANAL or OTOLITH), proprioceptive function (PROP), and age, with center of mass sway area (COM) measured with eyes open then closed on firm and then a foam surface. A cross-sectional sample of 366 community dwelling healthy adults from the Baltimore Longitudinal Study of Aging was tested. Multiple linear regressions examined the association between COM and VISFIELD, PROP, CANAL, and OTOLITH separately and in multi-sensory models controlling for age and gender. PROP dominated sensory prediction of sway across most balance conditions (β's = 0.09-0.19, p's < 0.001), except on foam eyes closed where CANAL function loss was the only significant sensory predictor of sway (β = 2.12, p < 0.016). Age was not a consistent predictor of sway. This suggests loss of peripheral sensory function explains much of the age-associated increase in sway.

  7. Axonal regeneration in severed peripheral facial nerve of the rabbit: relation of the number of axonal regenerates to behavioral and evoked muscle activity.

    PubMed

    Spector, J G; Lee, P

    1998-02-01

    The minimum number of regenerating facial nerve myelinated motor axons that are required to innervate and activate the mimetic musculature is not known. We compare rabbit facial nerve regeneration following complete transectional injuries of the buccal division to the evoked and behavioral muscle activities of the quadratus labii superioris muscle of the rabbit in three experimental models: end-to-end direct anastomosis (N = 4), 8-mm autologous nerve grafts (N = 8), and 10-mm silicone chamber implants (N = 40). Data are presented as total numbers of regenerating myelinated axons that traverse the surgical repair and innervate the fascicles of the transected distal nerve stump, as well as the percentage of regenerating neurites, as compared to the preoperative normal controls. Five weeks after neural repair, direct end-to-end anastomosis regained more myelinated axons across the reconstructed defect (2,632 +/- 1,232; 67%) than silicone tube implants (2,006 +/- 445; 51%) or autologous cable graft repairs (1,660 +/- 1,169; 42%). However, only a small percentage of myelinated fibers innervated the intrafascicular region of the distal transected neural stump in direct anastomosis (948 +/- 168; 24%), silicone tube implants (670 +/- 275; 17%), or autologous nerve grafts (445 +/- 120; 12%) in rabbits that regained evoked and behavioral mimetic muscle activity. All rabbits with direct anastomosis and neural cable grafts regained motor activity, despite the fact that 66% of regenerating motor neurites in cable graft repairs and 54% in direct anastomosis were collateral sprouts that did not contribute to effective muscle activity. In 17 rabbits with neural regenerates within the silicone tube implants that did not regain mimetic activity, the mean number of regenerating myelinated motor axons across the defect was 504 +/- 419 (13%), and the mean number of axons that innervated the distal transected nerve stump fascicles was 277 +/- 128 (7%). Therefore, the minimal number of

  8. Developmental time course of peripheral cross-modal sensory interaction of the trigeminal and gustatory systems.

    PubMed

    Omelian, Jacquelyn M; Berry, Marissa J; Gomez, Adam M; Apa, Kristi L; Sollars, Suzanne I

    2016-06-01

    Few sensory modalities appear to engage in cross-modal interactions within the peripheral nervous system, making the integrated relationship between the peripheral gustatory and trigeminal systems an ideal model for investigating cross-sensory support. The present study examined taste system anatomy following unilateral transection of the trigeminal lingual nerve (LX) while leaving the gustatory chorda tympani intact. At 10, 25, or 65 days of age, rats underwent LX with outcomes assessed following various survival times. Fungiform papillae were classified by morphological feature using surface analysis. Taste bud volumes were calculated from histological sections of the anterior tongue. Differences in papillae morphology were evident by 2 days post-transection of P10 rats and by 8 days post in P25 rats. When transected at P65, animals never exhibited statistically significant morphological changes. After LX at P10, fewer taste buds were present on the transected side following 16 and 24 days survival time and remaining taste buds were smaller than on the intact side. In P25 and P65 animals, taste bud volumes were reduced on the denervated side by 8 and 16 days postsurgery, respectively. By 50 days post-transection, taste buds of P10 animals had not recovered in size; however, all observed changes in papillae morphology and taste buds subsided in P25 and P65 rats. Results indicate that LX impacts taste receptor cells and alters epithelial morphology of fungiform papillae, particularly during early development. These findings highlight dual roles for the lingual nerve in the maintenance of both gustatory and non-gustatory tissues on the anterior tongue. © 2015 Wiley Periodicals, Inc.

  9. Peripheral optogenetic stimulation induces whisker movement and sensory perception in head-fixed mice

    PubMed Central

    Park, Sunmee; Bandi, Akhil; Lee, Christian R; Margolis, David J

    2016-01-01

    We discovered that optical stimulation of the mystacial pad in Emx1-Cre;Ai27D transgenic mice induces whisker movements due to activation of ChR2 expressed in muscles controlling retraction and protraction. Using high-speed videography in anesthetized mice, we characterize the amplitude of whisker protractions evoked by varying the intensity, duration, and frequency of optogenetic stimulation. Recordings from primary somatosensory cortex (S1) in anesthetized mice indicated that optogenetic whisker pad stimulation evokes robust yet longer latency responses than mechanical whisker stimulation. In head-fixed mice trained to report optogenetic whisker pad stimulation, psychometric curves showed similar dependence on stimulus duration as evoked whisker movements and S1 activity. Furthermore, optogenetic stimulation of S1 in expert mice was sufficient to substitute for peripheral stimulation. We conclude that whisker protractions evoked by optogenetic activation of whisker pad muscles results in cortical activity and sensory perception, consistent with the coding of evoked whisker movements by reafferent sensory input. DOI: http://dx.doi.org/10.7554/eLife.14140.001 PMID:27269285

  10. Histopathological findings in hereditary motor and sensory neuropathy of axonal type with onset in early childhood associated with mitofusin 2 mutations.

    PubMed

    Vallat, Jean-Michel; Ouvrier, Robert A; Pollard, John D; Magdelaine, Corinne; Zhu, Danqing; Nicholson, Garth A; Grew, Simon; Ryan, Monique M; Funalot, Benoît

    2008-11-01

    Neuropathologic abnormalities can be sufficiently characteristic to suggest the genetic basis of some hereditary neuropathies such as those associated with mutations in MPZ, GJB1, GDAP1, MTMR2, SH3TC2, PRX, FGD4, and LMNA. We analyzed the morphologic features of 9 sural nerve biopsies from 6 patients with mutations of mitofusin 2. All patients presented in early childhood with axonal neuropathies designated as mild or severe motor and sensory neuropathy. In all cases, there was a marked decrease in density of myelinated fibers, mainly of large diameter fibers. These changes were more marked in the second biopsies of 3 patients that were performed from 7 to 19 years after the first biopsies. Neurophysiologic findings were most suggestive of axonal degeneration, but some onion bulbs were present in all cases. Axonal mitochondria were smaller than normal, were round, and were abnormally aggregated. These changes may result from abnormal mitochondrial fusion and fission. The results suggest that these clinical and pathological features may be sufficiently characteristic to suggest the diagnosis of mitofusin 2-related neuropathy.

  11. Acute Putrescine Supplementation with Schwann Cell Implantation Improves Sensory and Serotonergic Axon Growth and Functional Recovery in Spinal Cord Injured Rats.

    PubMed

    Iorgulescu, J Bryan; Patel, Samik P; Louro, Jack; Andrade, Christian M; Sanchez, Andre R; Pearse, Damien D

    2015-01-01

    Schwann cell (SC) transplantation exhibits significant potential for spinal cord injury (SCI) repair and its use as a therapeutic modality has now progressed to clinical trials for subacute and chronic human SCI. Although SC implants provide a receptive environment for axonal regrowth and support functional recovery in a number of experimental SCI models, axonal regeneration is largely limited to local systems and the behavioral improvements are modest without additional combinatory approaches. In the current study we investigated whether the concurrent delivery of the polyamine putrescine, started either 30 min or 1 week after SCI, could enhance the efficacy of SCs when implanted subacutely (1 week after injury) into the contused rat spinal cord. Polyamines are ubiquitous organic cations that play an important role in the regulation of the cell cycle, cell division, cytoskeletal organization, and cell differentiation. We show that the combination of putrescine with SCs provides a significant increase in implant size, an enhancement in axonal (sensory and serotonergic) sparing and/or growth, and improved open field locomotion after SCI, as compared to SC implantation alone. These findings demonstrate that polyamine supplementation can augment the effectiveness of SCs when used as a therapeutic approach for subacute SCI repair.

  12. Acute Putrescine Supplementation with Schwann Cell Implantation Improves Sensory and Serotonergic Axon Growth and Functional Recovery in Spinal Cord Injured Rats

    PubMed Central

    Iorgulescu, J. Bryan; Patel, Samik P.; Louro, Jack; Andrade, Christian M.; Sanchez, Andre R.; Pearse, Damien D.

    2015-01-01

    Schwann cell (SC) transplantation exhibits significant potential for spinal cord injury (SCI) repair and its use as a therapeutic modality has now progressed to clinical trials for subacute and chronic human SCI. Although SC implants provide a receptive environment for axonal regrowth and support functional recovery in a number of experimental SCI models, axonal regeneration is largely limited to local systems and the behavioral improvements are modest without additional combinatory approaches. In the current study we investigated whether the concurrent delivery of the polyamine putrescine, started either 30 min or 1 week after SCI, could enhance the efficacy of SCs when implanted subacutely (1 week after injury) into the contused rat spinal cord. Polyamines are ubiquitous organic cations that play an important role in the regulation of the cell cycle, cell division, cytoskeletal organization, and cell differentiation. We show that the combination of putrescine with SCs provides a significant increase in implant size, an enhancement in axonal (sensory and serotonergic) sparing and/or growth, and improved open field locomotion after SCI, as compared to SC implantation alone. These findings demonstrate that polyamine supplementation can augment the effectiveness of SCs when used as a therapeutic approach for subacute SCI repair. PMID:26550496

  13. Modulating molecular chaperones improves sensory fiber recovery and mitochondrial function in diabetic peripheral neuropathy

    PubMed Central

    Urban, Michael J.; Pan, Pan; Farmer, Kevin L.; Zhao, Huiping; Blagg, Brian S.J.; Dobrowsky, Rick T.

    2012-01-01

    Quantification of intra-epidermal nerve fibers (iENFs) is an important approach to stage diabetic peripheral neuropathy (DPN) and is a promising clinical endpoint for identifying beneficial therapeutics. Mechanistically, diabetes decreases neuronal mitochondrial function and enhancing mitochondrial respiratory capacity may aid neuronal recovery from glucotoxic insults. We have proposed that modulating the activity and expression of heat shock proteins (Hsp) may be of benefit in treating DPN. KU-32 is a C-terminal Hsp90 inhibitor that improved thermal hypoalgesia in diabetic C57Bl/6 mice but it was not determined if this was associated with an increase in iENF density and mitochondrial function. After 16 weeks of diabetes, Swiss Webster mice showed decreased electrophysiological and psychosensory responses and a >30% loss of iENFs. Treatment of the mice with ten weekly doses of 20 mg/kg KU-32 significantly reversed pre-existing deficits in nerve conduction velocity and responses to mechanical and thermal stimuli. KU-32 therapy significantly reversed the pre-existing loss of iENFs despite the identification of a sub-group of drug-treated diabetic mice that showed improved thermal sensitivity but no increase in iENF density. To determine if the improved clinical indices correlated with enhanced mitochondrial activity, sensory neurons were isolated and mitochondrial bioenergetics assessed ex vivo using extracellular flux technology. Diabetes decreased maximal respiratory capacity in sensory neurons and this deficit was improved following KU-32 treatment. In conclusion, KU-32 improved physiological and morphologic markers of degenerative neuropathy and drug efficacy may be related to enhanced mitochondrial bioenergetics in sensory neurons. PMID:22465570

  14. Modulating molecular chaperones improves sensory fiber recovery and mitochondrial function in diabetic peripheral neuropathy.

    PubMed

    Urban, Michael J; Pan, Pan; Farmer, Kevin L; Zhao, Huiping; Blagg, Brian S J; Dobrowsky, Rick T

    2012-05-01

    Quantification of intra-epidermal nerve fibers (iENFs) is an important approach to stage diabetic peripheral neuropathy (DPN) and is a promising clinical endpoint for identifying beneficial therapeutics. Mechanistically, diabetes decreases neuronal mitochondrial function and enhancing mitochondrial respiratory capacity may aid neuronal recovery from glucotoxic insults. We have proposed that modulating the activity and expression of heat shock proteins (Hsp) may be of benefit in treating DPN. KU-32 is a C-terminal Hsp90 inhibitor that improved thermal hypoalgesia in diabetic C57Bl/6 mice but it was not determined if this was associated with an increase in iENF density and mitochondrial function. After 16 weeks of diabetes, Swiss Webster mice showed decreased electrophysiological and psychosensory responses and a >30% loss of iENFs. Treatment of the mice with ten weekly doses of 20mg/kg KU-32 significantly reversed pre-existing deficits in nerve conduction velocity and responses to mechanical and thermal stimuli. KU-32 therapy significantly reversed the pre-existing loss of iENFs despite the identification of a sub-group of drug-treated diabetic mice that showed improved thermal sensitivity but no increase in iENF density. To determine if the improved clinical indices correlated with enhanced mitochondrial activity, sensory neurons were isolated and mitochondrial bioenergetics assessed ex vivo using extracellular flux technology. Diabetes decreased maximal respiratory capacity in sensory neurons and this deficit was improved following KU-32 treatment. In conclusion, KU-32 improved physiological and morphologic markers of degenerative neuropathy and drug efficacy may be related to enhanced mitochondrial bioenergetics in sensory neurons.

  15. Repetitive activity slows axonal conduction velocity and concomitantly increases mechanical activation threshold in single axons of the rat cranial dura.

    PubMed

    De Col, Roberto; Messlinger, Karl; Carr, Richard W

    2012-02-15

    The passage of an action potential along a peripheral axon modulates the conduction velocity of subsequent action potentials. In C-neurones with unmyelinated axons repetitive activity progressively slows axonal conduction velocity and in microneurographic recordings from healthy human subjects the magnitude of this slowing can be used to predict the receptive properties of individual axons. Recently, a reduction in the number of available voltage-gated sodium channels (Na(V)) through inactivation has been implicated as the predominant factor responsible for the slowing of axonal conduction. Since Na(V)s are also responsible for the initiation of action potentials in sensory nerve terminals, changes in their availability may be expected to affect activation threshold for sensory stimuli. To examine this proposal, dynamic mechanical stimuli were used to make precise estimates of activation threshold in single unmyelinated axons innervating the rat cranial dura mater. Decreases in axonal conduction velocity induced by repetitive electrical stimulation were paralleled by an increase in mechanical activation threshold. Application of TTX (10-20 nM) also slowed axonal conduction velocity in all 11 fibres examined and in 9 of these this resulted in a parallel increase in mechanical activation threshold. We interpret this as indicating that a reduction in available Na(V) number contributes to both axonal conduction velocity slowing and the observed parallel increase in mechanical activation threshold. The slowing of axonal conduction velocity observed during repetitive activity thus represents a form of accommodation, i.e. self inhibition, which is likely to be decisive in limiting peripheral input to the spinal dorsal horn and thereby regulating processes that could otherwise lead to central sensitization.

  16. Identification of genes influencing dendrite morphogenesis in developing peripheral sensory and central motor neurons

    PubMed Central

    Ou, Yimiao; Chwalla, Barbara; Landgraf, Matthias; van Meyel, Donald J

    2008-01-01

    Background Developing neurons form dendritic trees with cell type-specific patterns of growth, branching and targeting. Dendrites of Drosophila peripheral sensory neurons have emerged as a premier genetic model, though the molecular mechanisms that underlie and regulate their morphogenesis remain incompletely understood. Still less is known about this process in central neurons and the extent to which central and peripheral dendrites share common organisational principles and molecular features. To address these issues, we have carried out two comparable gain-of-function screens for genes that influence dendrite morphologies in peripheral dendritic arborisation (da) neurons and central RP2 motor neurons. Results We found 35 unique loci that influenced da neuron dendrites, including five previously shown as required for da dendrite patterning. Several phenotypes were class-specific and many resembled those of known mutants, suggesting that genes identified in this study may converge with and extend known molecular pathways for dendrite development in da neurons. The second screen used a novel technique for cell-autonomous gene misexpression in RP2 motor neurons. We found 51 unique loci affecting RP2 dendrite morphology, 84% expressed in the central nervous system. The phenotypic classes from both screens demonstrate that gene misexpression can affect specific aspects of dendritic development, such as growth, branching and targeting. We demonstrate that these processes are genetically separable. Targeting phenotypes were specific to the RP2 screen, and we propose that dendrites in the central nervous system are targeted to territories defined by Cartesian co-ordinates along the antero-posterior and the medio-lateral axes of the central neuropile. Comparisons between the screens suggest that the dendrites of peripheral da and central RP2 neurons are shaped by regulatory programs that only partially overlap. We focused on one common candidate pathway controlled by the

  17. In vivo stimulation of early peripheral axon regeneration by N-propionylmannosamine in the presence of polysialyltransferase ST8SIA2.

    PubMed

    Koulaxouzidis, Georgios; Reutter, Werner; Hildebrandt, Herbert; Stark, G Björn; Witzel, Christian

    2015-09-01

    The key enzyme of sialic acid (Sia) biosynthesis is the bifunctional UDP-N-acetylglucosamine 2-epimerase/ManNAc kinase (GNE/MNK). It metabolizes the physiological precursor ManNAc and N-acyl modified analogues such as N-propionylmannosamine (ManNProp) to the respective modified sialic acid. Polysialic acid (polySia) is a crucial compound for several functions in the nervous system and is synthesized by the polysialyltransferases ST8SIA2 and ST8SIA4. PolySia can be modified in vitro and in vivo by metabolic glycoengineering of the N-acyl side chain of Sia. In vitro studies show that the application of ManNProp increases neurite outgrowth and accelerates the re-establishment of functional synapses. In this study, we investigate in vivo how ManNProp application might benefit peripheral nerve regeneration. In mice expressing axonal fluorescent proteins (thy-1-YFP), we transected the sciatic nerve and then replaced part of it with a sciatic nerve graft from non-expressing mice (wild-type mice or St8sia2(-/-) mice). Analyses conducted 5 days after grafting showed that systemic application of ManNProp (200 mg/kg, twice a day, i.p.), but not of physiological ManNAc (1 g/kg, twice a day, i.p.), significantly increased the extent of axonal elongation, the number of arborizing axons and the number of branches per regenerating axon within the grafts from wild-type mice, but not in those from St8sia2(-/-) mice. The results demonstrate that the application of ManNProp has beneficial effects on early peripheral nerve regeneration and indicate that the stimulation of axon growth depends on ST8SIA2 activity in the nerve graft.

  18. Fast-spiking GABA circuit dynamics in the auditory cortex predict recovery of sensory processing following peripheral nerve damage.

    PubMed

    Resnik, Jennifer; Polley, Daniel B

    2017-03-21

    Cortical neurons remap their receptive fields and rescale sensitivity to spared peripheral inputs following sensory nerve damage. To address how these plasticity processes are coordinated over the course of functional recovery, we tracked receptive field reorganization, spontaneous activity, and response gain from individual principal neurons in the adult mouse auditory cortex over a 50-day period surrounding either moderate or massive auditory nerve damage. We related the day-by-day recovery of sound processing to dynamic changes in the strength of intracortical inhibition from parvalbumin-expressing (PV) inhibitory neurons. Whereas the status of brainstem-evoked potentials did not predict the recovery of sensory responses to surviving nerve fibers, homeostatic adjustments in PV-mediated inhibition during the first days following injury could predict the eventual recovery of cortical sound processing weeks later. These findings underscore the potential importance of self-regulated inhibitory dynamics for the restoration of sensory processing in excitatory neurons following peripheral nerve injuries.

  19. Methods to measure peripheral and central sensitization using quantitative sensory testing: A focus on individuals with low back pain.

    PubMed

    Starkweather, Angela R; Heineman, Amy; Storey, Shannon; Rubia, Gil; Lyon, Debra E; Greenspan, Joel; Dorsey, Susan G

    2016-02-01

    Quantitative sensory testing can be used to assess peripheral and central sensitization; important factors that contribute to the individual's experience of pain and disability. Many studies use quantitative sensory testing in patients with low back pain to detect alterations in pain sensitivity, however, because investigators employ different protocols, interpretation of findings across studies can become problematic. The purpose of this article is to propose a standardized method of testing peripheral and central pain sensitization in patients with low back pain. Video clips are provided to demonstrate correct procedures for measuring the response to experimental pain using mechanical, thermal and pressure modalities. As nurse researchers and clinicians increase utilization of quantitative sensory testing to examine pain phenotypes, it is anticipated that more personalized methods for monitoring the trajectory of low back pain and response to treatment will improve outcomes for this patient population.

  20. Genome-wide association study identifies ephrin type A receptors implicated in paclitaxel induced peripheral sensory neuropathy.

    PubMed

    Leandro-García, Luis J; Inglada-Pérez, Lucía; Pita, Guillermo; Hjerpe, Elisabet; Leskelä, Susanna; Jara, Carlos; Mielgo, Xabier; González-Neira, Anna; Robledo, Mercedes; Avall-Lundqvist, Elisabeth; Gréen, Henrik; Rodríguez-Antona, Cristina

    2013-09-01

    Peripheral neuropathy is the dose limiting toxicity of paclitaxel, a chemotherapeutic drug widely used to treat solid tumours. This toxicity exhibits great inter-individual variability of unknown origin. The present study aimed to identify genetic variants associated with paclitaxel induced neuropathy via a whole genome approach. A genome-wide association study (GWAS) was performed in 144 white European patients uniformly treated with paclitaxel/carboplatin and for whom detailed data on neuropathy was available. Per allele single nucleotide polymorphism (SNP) associations were assessed by Cox regression, modelling the cumulative dose of paclitaxel up to the development of grade 2 sensory neuropathy. The strongest evidence of association was observed for the ephrin type A receptor 4 (EPHA4) locus (rs17348202, p=1.0×10(-6)), and EPHA6 and EPHA5 were among the top 25 and 50 hits (rs301927, p=3.4×10(-5) and rs1159057, p=6.8×10(-5)), respectively. A meta-analysis of EPHA5-rs7349683, the top marker for paclitaxel induced neuropathy in a previous GWAS (r(2)=0.79 with rs1159057), gave a hazard ratio (HR) estimate of 1.68 (p=1.4×10(-9)). Meta-analysis of the second hit of this GWAS, XKR4-rs4737264, gave a HR of 1.71 (p=3.1×10(-8)). Imputed SNPs at LIMK2 locus were also strongly associated with this toxicity (HR=2.78, p=2.0×10(-7)). This study provides independent support of EPHA5-rs7349683 and XKR4-rs4737264 as the first markers of risk of paclitaxel induced neuropathy. In addition, it suggests that other EPHA genes also involved in axonal guidance and repair following neural injury, as well as LIMK2 locus, may play an important role in the development of this toxicity. The identified SNPs could form the basis for individualised paclitaxel chemotherapy.

  1. The Influence of Diabetic Peripheral Neuropathy on Local Postural Muscle and Central Sensory Feedback Balance Control

    PubMed Central

    2015-01-01

    Poor balance control and increased fall risk have been reported in people with diabetic peripheral neuropathy (DPN). Traditional body sway measures are unable to describe underlying postural control mechanism. In the current study, we used stabilogram diffusion analysis to examine the mechanism under which balance is altered in DPN patients under local-control (postural muscle control) and central-control (postural control using sensory cueing). DPN patients and healthy age-matched adults over 55 years performed two 15-second Romberg balance trials. Center of gravity sway was measured using a motion tracker system based on wearable inertial sensors, and used to derive body sway and local/central control balance parameters. Eighteen DPN patients (age = 65.4±7.6 years; BMI = 29.3±5.3 kg/m2) and 18 age-matched healthy controls (age = 69.8±2.9; BMI = 27.0±4.1 kg/m2) with no major mobility disorder were recruited. The rate of sway within local-control was significantly higher in the DPN group by 49% (healthy local-controlslope = 1.23±1.06×10-2 cm2/sec, P<0.01), which suggests a compromised local-control balance behavior in DPN patients. Unlike local-control, the rate of sway within central-control was 60% smaller in the DPN group (healthy central-controlslope-Log = 0.39±0.23, P<0.02), which suggests an adaptation mechanism to reduce the overall body sway in DPN patients. Interestingly, significant negative correlations were observed between central-control rate of sway with neuropathy severity (rPearson = 0.65-085, P<0.05) and the history of diabetes (rPearson = 0.58-071, P<0.05). Results suggest that in the lack of sensory feedback cueing, DPN participants were highly unstable compared to controls. However, as soon as they perceived the magnitude of sway using sensory feedback, they chose a high rigid postural control strategy, probably due to high concerns for fall, which may increase the energy cost during extended period of standing; the adaptation mechanism

  2. The influence of diabetic peripheral neuropathy on local postural muscle and central sensory feedback balance control.

    PubMed

    Toosizadeh, Nima; Mohler, Jane; Armstrong, David G; Talal, Talal K; Najafi, Bijan

    2015-01-01

    Poor balance control and increased fall risk have been reported in people with diabetic peripheral neuropathy (DPN). Traditional body sway measures are unable to describe underlying postural control mechanism. In the current study, we used stabilogram diffusion analysis to examine the mechanism under which balance is altered in DPN patients under local-control (postural muscle control) and central-control (postural control using sensory cueing). DPN patients and healthy age-matched adults over 55 years performed two 15-second Romberg balance trials. Center of gravity sway was measured using a motion tracker system based on wearable inertial sensors, and used to derive body sway and local/central control balance parameters. Eighteen DPN patients (age = 65.4±7.6 years; BMI = 29.3±5.3 kg/m2) and 18 age-matched healthy controls (age = 69.8±2.9; BMI = 27.0±4.1 kg/m2) with no major mobility disorder were recruited. The rate of sway within local-control was significantly higher in the DPN group by 49% (healthy local-controlslope = 1.23±1.06×10-2 cm2/sec, P<0.01), which suggests a compromised local-control balance behavior in DPN patients. Unlike local-control, the rate of sway within central-control was 60% smaller in the DPN group (healthy central-controlslope-Log = 0.39±0.23, P<0.02), which suggests an adaptation mechanism to reduce the overall body sway in DPN patients. Interestingly, significant negative correlations were observed between central-control rate of sway with neuropathy severity (rPearson = 0.65-085, P<0.05) and the history of diabetes (rPearson = 0.58-071, P<0.05). Results suggest that in the lack of sensory feedback cueing, DPN participants were highly unstable compared to controls. However, as soon as they perceived the magnitude of sway using sensory feedback, they chose a high rigid postural control strategy, probably due to high concerns for fall, which may increase the energy cost during extended period of standing; the adaptation mechanism

  3. Comparison of sensory tests and neuronal quantity of peripheral nerves between streptozotocin (STZ)-induced diabetic rats and paclitaxel (PAC)-treated rats.

    PubMed

    Jin, Heung Yong; Lee, Na Young; Ko, Hyun A; Lee, Kyung Ae; Park, Tae Sun

    Although diabetic peripheral neuropathy (DPN) and chemotherapy-induced peripheral neuropathy (CIPN) are different disease entities, they share similar neuropathic symptoms that impede quality of life for these patients. Despite having very similar downstream effects, there have been no direct comparisons between DPN and CIPN with respect to symptom severity and therapeutic responses. We compared peripheral nerve damage due to hyperglycemia with that caused by paclitaxel (PAC) treatment as represented by biochemical parameters, diverse sensory tests, and immunohistochemistry of cutaneous and sciatic nerves. The therapeutic effects of alpha-lipoic acid and DA-9801 were also compared in the two models. Animals were divided into seven groups (n = 7-10) as follows: normal, diabetes (DM), DM + alpha-lipoic acid 100 mg/kg (ALA), DM + DA-9801 (100 mg/kg), paclitaxel-treated rat (PAC), PAC + ALA (100 mg/kg), and PAC + DA-9801 (100 mg/kg). The sensory thresholds of animals to mechanical, heat, and pressure stimuli were altered by both hyperglycemia and PAC when compared with controls, and the responses to sensory tests were different between both groups. There were no significant differences in the biochemical markers of blood glutathione between DM and PAC groups (p > .05). Quantitative comparisons of peripheral nerves by intraepidermal nerve fiber density (IENFD) analysis indicated that the DM and PAC groups were similar (6.18 ± 1.03 vs. 5.01 ± 2.57). IENFD was significantly improved after ALA and DA-9801 treatment in diabetic animals (7.6 ± 1.28, 7.7 ± 1.28, respectively, p < .05) but did not reach significance in the PAC-treated groups (6.05 ± 1.76, 5.66 ± 1.26, respectively, p > .05). Sciatic nerves were less damaged in the PAC-treated groups compared with the DM groups with respect to axonal diameter and area (8.60 ± 1.14 μm vs. 6.66 ± 1.07 μm, and 59.04 ± 15.16 μm(2) vs. 35

  4. The role of microstructured and interconnected pore channels in a collagen-based nerve guide on axonal regeneration in peripheral nerves.

    PubMed

    Bozkurt, Ahmet; Lassner, Franz; O'Dey, Dan; Deumens, Ronald; Böcker, Arne; Schwendt, Tilman; Janzen, Christoph; Suschek, Christoph V; Tolba, Rene; Kobayashi, Eiji; Sellhaus, Bernd; Tholl, S; Eummelen, Lizette; Schügner, Frank; Damink, Leon Olde; Weis, Joachim; Brook, Gary A; Pallua, Norbert

    2012-02-01

    The use of bioengineered nerve guides as alternatives for autologous nerve transplantation (ANT) is a promising strategy for the repair of peripheral nerve defects. In the present investigation, we present a collagen-based micro-structured nerve guide (Perimaix) for the repair of 2 cm rat sciatic nerve defects. Perimaix is an open-porous biodegradable nerve guide containing continuous, longitudinally orientated channels for orientated nerve growth. The effects of these nerve guides on axon regeneration by six weeks after implantation have been compared with those of ANT. Investigation of the regenerated sciatic nerve indicated that Perimaix strongly supported directed axon regeneration. When seeded with cultivated rat Schwann cells (SC), the Perimaix nerve guide was found to be almost as supportive of axon regeneration as ANT. The use of SC from transgenic green-fluorescent-protein (GFP) rats allowed us to detect the viability of donor SC at 1 week and 6 weeks after transplantation. The GFP-positive SC were aligned in a columnar fashion within the longitudinally orientated micro-channels. This cellular arrangement was not only observed prior to implantation, but also at one week and 6 weeks after implantation. It may be concluded that Perimaix nerve guides hold great promise for the repair of peripheral nerve defects.

  5. VEGF induces sensory and motor peripheral plasticity, alters bladder function, and promotes visceral sensitivity

    PubMed Central

    2012-01-01

    Background This work tests the hypothesis that bladder instillation with vascular endothelial growth factor (VEGF) modulates sensory and motor nerve plasticity, and, consequently, bladder function and visceral sensitivity. In addition to C57BL/6J, ChAT-cre mice were used for visualization of bladder cholinergic nerves. The direct effect of VEGF on the density of sensory nerves expressing the transient receptor potential vanilloid subfamily 1 (TRPV1) and cholinergic nerves (ChAT) was studied one week after one or two intravesical instillations of the growth factor. To study the effects of VEGF on bladder function, mice were intravesically instilled with VEGF and urodynamic evaluation was assessed. VEGF-induced alteration in bladder dorsal root ganglion (DRG) neurons was performed on retrogradly labeled urinary bladder afferents by patch-clamp recording of voltage gated Na+ currents. Determination of VEGF-induced changes in sensitivity to abdominal mechanostimulation was performed by application of von Frey filaments. Results In addition to an overwhelming increase in TRPV1 immunoreactivity, VEGF instillation resulted in an increase in ChAT-directed expression of a fluorescent protein in several layers of the urinary bladder. Intravesical VEGF caused a profound change in the function of the urinary bladder: acute VEGF (1 week post VEGF treatment) reduced micturition pressure and longer treatment (2 weeks post-VEGF instillation) caused a substantial reduction in inter-micturition interval. In addition, intravesical VEGF resulted in an up-regulation of voltage gated Na+ channels (VGSC) in bladder DRG neurons and enhanced abdominal sensitivity to mechanical stimulation. Conclusions For the first time, evidence is presented indicating that VEGF instillation into the mouse bladder promotes a significant increase in peripheral nerve density together with alterations in bladder function and visceral sensitivity. The VEGF pathway is being proposed as a key modulator of

  6. MicroRNA-431 regulates axon regeneration in mature sensory neurons by targeting the Wnt antagonist Kremen1

    PubMed Central

    Wu, Di; Murashov, Alexander K.

    2013-01-01

    MicroRNAs (miRNAs) are small, non-coding RNAs that function as key post-transcriptional regulators in neural development, brain function, and neurological diseases. Growing evidence indicates that miRNAs are also important mediators of nerve regeneration, however, the affected signaling mechanisms are not clearly understood. In the present study, we show that nerve injury-induced miR-431 stimulates regenerative axon growth by silencing Kremen1, an antagonist of Wnt/beta-catenin signaling. Both the gain-of-function of miR-431 and knockdown of Kremen1 significantly enhance axon outgrowth in murine dorsal root ganglion neuronal cultures. Using cross-linking with AGO-2 immunoprecipitation, and 3′-untranslated region (UTR) luciferase reporter assay we demonstrate miR-431 direct interaction on the 3′-UTR of Kremen1 mRNA. Together, our results identify miR-431 as an important regulator of axonal regeneration and a promising therapeutic target. PMID:24167472

  7. TMEM184b Promotes Axon Degeneration and Neuromuscular Junction Maintenance.

    PubMed

    Bhattacharya, Martha R C; Geisler, Stefanie; Pittman, Sara K; Doan, Ryan A; Weihl, Conrad C; Milbrandt, Jeffrey; DiAntonio, Aaron

    2016-04-27

    Complex nervous systems achieve proper connectivity during development and must maintain these connections throughout life. The processes of axon and synaptic maintenance and axon degeneration after injury are jointly controlled by a number of proteins within neurons, including ubiquitin ligases and mitogen activated protein kinases. However, our understanding of these molecular cascades is incomplete. Here we describe the phenotype resulting from mutation of TMEM184b, a protein identified in a screen for axon degeneration mediators. TMEM184b is highly expressed in the mouse nervous system and is found in recycling endosomes in neuronal cell bodies and axons. Disruption of TMEM184b expression results in prolonged maintenance of peripheral axons following nerve injury, demonstrating a role for TMEM184b in axon degeneration. In contrast to this protective phenotype in axons, uninjured mutant mice have anatomical and functional impairments in the peripheral nervous system. Loss of TMEM184b causes swellings at neuromuscular junctions that become more numerous with age, demonstrating that TMEM184b is critical for the maintenance of synaptic architecture. These swellings contain abnormal multivesicular structures similar to those seen in patients with neurodegenerative disorders. Mutant animals also show abnormal sensory terminal morphology. TMEM184b mutant animals are deficient on the inverted screen test, illustrating a role for TMEM184b in sensory-motor function. Overall, we have identified an important function for TMEM184b in peripheral nerve terminal structure, function, and the axon degeneration pathway. Our work has identified both neuroprotective and neurodegenerative roles for a previously undescribed protein, TMEM184b. TMEM184b mutation causes delayed axon degeneration following peripheral nerve injury, indicating that it participates in the degeneration process. Simultaneously, TMEM184b mutation causes progressive structural abnormalities at neuromuscular

  8. Sensory feedback by peripheral nerve stimulation improves task performance in individuals with upper limb loss using a myoelectric prosthesis

    PubMed Central

    Schiefer, Matthew; Tan, Daniel; Sidek, Steven M; Tyler, Dustin J

    2017-01-01

    Objective Tactile feedback is critical to grip and object manipulation. Its absence results in reliance on visual and auditory cues. Our objective was to assess the effect of sensory feedback on task performance in individuals with limb loss. Approach Stimulation of the peripheral nerves using implanted cuff electrodes provided two subjects with sensory feedback with intensity proportional to forces on the thumb, index, and middle fingers of their prosthetic hand during object manipulation. Both subjects perceived the sensation on their phantom hand at locations corresponding to the locations of the forces on the prosthetic hand. A bend sensor measured prosthetic hand span. Hand span modulated the intensity of sensory feedback perceived on the thenar eminence for subject 1 and the middle finger for subject 2. We performed three functional tests with the blindfolded subjects. First, the subject tried to determine whether or not a wooden block had been placed in his prosthetic hand. Second, the subject had to locate and remove magnetic blocks from a metal table. Third, the subject performed the Southampton Hand Assessment Procedure (SHAP). We also measured the subject’s sense of embodiment with a survey and his self-confidence. Main results Blindfolded performance with sensory feedback was similar to sighted performance in the wooden block and magnetic block tasks. Performance on the SHAP, a measure of hand mechanical function and control, was similar with and without sensory feedback. An embodiment survey showed an improved sense of integration of the prosthesis in self body image with sensory feedback. Significance Sensory feedback by peripheral nerve stimulation improved object discrimination and manipulation, embodiment, and confidence. With both forms of feedback, the blindfolded subjects tended toward results obtained with visual feedback. PMID:26643802

  9. Sensory feedback by peripheral nerve stimulation improves task performance in individuals with upper limb loss using a myoelectric prosthesis

    NASA Astrophysics Data System (ADS)

    Schiefer, Matthew; Tan, Daniel; Sidek, Steven M.; Tyler, Dustin J.

    2016-02-01

    Objective. Tactile feedback is critical to grip and object manipulation. Its absence results in reliance on visual and auditory cues. Our objective was to assess the effect of sensory feedback on task performance in individuals with limb loss. Approach. Stimulation of the peripheral nerves using implanted cuff electrodes provided two subjects with sensory feedback with intensity proportional to forces on the thumb, index, and middle fingers of their prosthetic hand during object manipulation. Both subjects perceived the sensation on their phantom hand at locations corresponding to the locations of the forces on the prosthetic hand. A bend sensor measured prosthetic hand span. Hand span modulated the intensity of sensory feedback perceived on the thenar eminence for subject 1 and the middle finger for subject 2. We performed three functional tests with the blindfolded subjects. First, the subject tried to determine whether or not a wooden block had been placed in his prosthetic hand. Second, the subject had to locate and remove magnetic blocks from a metal table. Third, the subject performed the Southampton Hand Assessment Procedure (SHAP). We also measured the subject’s sense of embodiment with a survey and his self-confidence. Main results. Blindfolded performance with sensory feedback was similar to sighted performance in the wooden block and magnetic block tasks. Performance on the SHAP, a measure of hand mechanical function and control, was similar with and without sensory feedback. An embodiment survey showed an improved sense of integration of the prosthesis in self body image with sensory feedback. Significance. Sensory feedback by peripheral nerve stimulation improved object discrimination and manipulation, embodiment, and confidence. With both forms of feedback, the blindfolded subjects tended toward results obtained with visual feedback.

  10. A distal Schwann cell-specific enhancer mediates axonal regulation of the Oct-6 transcription factor during peripheral nerve development and regeneration

    PubMed Central

    Mandemakers, Wim; Zwart, Ronald; Jaegle, Martine; Walbeehm, Erik; Visser, Pim; Grosveld, Frank; Meijer, Dies

    2000-01-01

    The POU domain transcription factor Oct-6 is a major regulator of Schwann cell differentiation and myelination. During nerve development and regeneration, expression of Oct-6 is under the control of axonal signals. Identification of the cis-acting elements necessary for Oct-6 gene regulation is an important step in deciphering the complex signalling between Schwann cells and axons governing myelination. Here we show that a fragment distal to the Oct-6 gene, containing two DNase I-hypersensitive sites, acts as the Oct-6 Schwann cell-specific enhancer (SCE). The SCE is sufficient to drive spatially and temporally correct expression, during both normal peripheral nerve development and regeneration. We further demonstrate that a tagged version of Oct-6, driven by the SCE, rescues the peripheral nerve phenotype of Oct-6-deficient mice. Thus, our isolation and characterization of the Oct-6 SCE provides the first description of a cis-acting genetic element that responds to converging signalling pathways to drive myelination in the peripheral nervous system. PMID:10856243

  11. The effects of electroacupuncture on analgesia and peripheral sensory thresholds in patients with burn scar pain.

    PubMed

    Cuignet, Olivier; Pirlot, A; Ortiz, S; Rose, T

    2015-09-01

    The aim of this study is to observe if the effects of electro-acupuncture (EA) on analgesia and peripheral sensory thresholds are transposable from the model of heat pain in volunteers to the clinical setting of burn scar pain. After severe burns, pathological burn scars (PPBS) may occur with excruciating pain that respond poorly to treatment and prevent patients from wearing their pressure garments, thereby leading to unesthetic and function-limiting scars. EA might be of greater benefit in terms of analgesia and functional recovery, should it interrupt this vicious circle by counteracting the peripheral hyperalgesia characterizing PPBS. Therefore we enrolled 32 patients (22 males/10 females) aged of 46±11 years with clinical signs of PPBS and of neuropathic pain despite treatment. The study protocol consisted in 3 weekly 30-min sessions of standardized EA with extra individual needles in accordance to Traditional Chinese Medicine, in addition of previous treatments. We assessed VAS for pain and quantitative sensory testing (QST) twice: one week before and one after protocol. QST measured electrical thresholds for non-nociceptive A-beta fibers, nociceptive A-delta and C fibers in 2 dermatomes, respectively from the PPBS and from the contralateral pain-free areas. Based on heat pain studies, EA consisted in sessions at the extremity points of the main meridian flowing through PPBS (0.300s, 5Hz, sub noxious intensity, 15min) and at the bilateral paravertebral points corresponding to the same metameric level, 15min. VAS reduction of 3 points or below 3 on a 10 points scale was considered clinically relevant. Paired t-test compared thresholds (mean [SD]) and Wilcoxon test compared VAS (median [IQR]) pre and after treatment, significant p<0.05. The reduction of VAS for pain reached statistical but not clinical relevance (6.8 [3] vs. 4.5 [3.6]). This was due to a large subgroup of 14 non-responders whose VAS did not change after treatment (6.6 [2.7] vs. 7.2 [3

  12. Axonal morphological changes following impulse activity in mouse peripheral nerve in vivo: the return pathway for sodium ions.

    PubMed

    Trigo, Diogo; Smith, Kenneth J

    2015-02-15

    Conduction in myelinated axons involves substantial ion movements that must be reversed to restore homeostasis. The pathway taken by sodium ions returning to their original location and the potential osmotic consequences are currently unknown. We report striking morphological changes in axons following sustained impulse conduction that appear to result from osmosis and to indicate accumulation of ions in the periaxonal space followed by their release at the paranode. We conclude that the morphological changes illustrate a hitherto unrecognized part of normal axonal physiology that may also indicate the return pathway for the sodium ions involved in impulse formation. Myelinated axons can conduct sustained trains of impulses at high frequency, but this involves substantial ion movements that must be reversed to restore homeostasis. Little attention has been paid to the potential osmotic consequences of the ion movements or to the pathway taken by sodium ions returning to their original endoneurial location, given that the axolemmal Na(+)-K(+)-ATPase extrudes these ions into the periaxonal space beneath the myelin rather than into the endoneurium. Serial confocal imaging of fluorescent axons conducting at sustained physiological frequencies in vivo has revealed surprising morphological changes that may illuminate these problems. Saphenous nerves and spinal roots of anaesthetized transgenic mice expressing axoplasmic yellow fluorescent protein were stimulated electrically or pharmacologically (veratridine). Within 2 h, the axon herniated on one or both sides of the nodal membrane, displacing the paranodal myelin and widening the nodal gap. The herniated axoplasm became directed back towards the internode, forming a 'cap' up to 30 μm long. Concurrently, the fluid in the expanded periaxonal space accumulated into droplets that appeared to travel to the paranode, where they escaped. No such alterations occurred in axons treated with sodium channel or Na

  13. Primary sensory and motor cortex excitability are co-modulated in response to peripheral electrical nerve stimulation.

    PubMed

    Schabrun, Siobhan M; Ridding, Michael C; Galea, Mary P; Hodges, Paul W; Chipchase, Lucinda S

    2012-01-01

    Peripheral electrical stimulation (PES) is a common clinical technique known to induce changes in corticomotor excitability; PES applied to induce a tetanic motor contraction increases, and PES at sub-motor threshold (sensory) intensities decreases, corticomotor excitability. Understanding of the mechanisms underlying these opposite changes in corticomotor excitability remains elusive. Modulation of primary sensory cortex (S1) excitability could underlie altered corticomotor excitability with PES. Here we examined whether changes in primary sensory (S1) and motor (M1) cortex excitability follow the same time-course when PES is applied using identical stimulus parameters. Corticomotor excitability was measured using transcranial magnetic stimulation (TMS) and sensory cortex excitability using somatosensory evoked potentials (SEPs) before and after 30 min of PES to right abductor pollicis brevis (APB). Two PES paradigms were tested in separate sessions; PES sufficient to induce a tetanic motor contraction (30-50 Hz; strong motor intensity) and PES at sub motor-threshold intensity (100 Hz). PES applied to induce strong activation of APB increased the size of the N(20)-P(25) component, thought to reflect sensory processing at cortical level, and increased corticomotor excitability. PES at sensory intensity decreased the size of the P25-N33 component and reduced corticomotor excitability. A positive correlation was observed between the changes in amplitude of the cortical SEP components and corticomotor excitability following sensory and motor PES. Sensory PES also increased the sub-cortical P(14)-N(20) SEP component. These findings provide evidence that PES results in co-modulation of S1 and M1 excitability, possibly due to cortico-cortical projections between S1 and M1. This mechanism may underpin changes in corticomotor excitability in response to afferent input generated by PES.

  14. Primary Sensory and Motor Cortex Excitability Are Co-Modulated in Response to Peripheral Electrical Nerve Stimulation

    PubMed Central

    Schabrun, Siobhan M.; Ridding, Michael C.; Galea, Mary P.; Hodges, Paul W.; Chipchase, Lucinda S.

    2012-01-01

    Peripheral electrical stimulation (PES) is a common clinical technique known to induce changes in corticomotor excitability; PES applied to induce a tetanic motor contraction increases, and PES at sub-motor threshold (sensory) intensities decreases, corticomotor excitability. Understanding of the mechanisms underlying these opposite changes in corticomotor excitability remains elusive. Modulation of primary sensory cortex (S1) excitability could underlie altered corticomotor excitability with PES. Here we examined whether changes in primary sensory (S1) and motor (M1) cortex excitability follow the same time-course when PES is applied using identical stimulus parameters. Corticomotor excitability was measured using transcranial magnetic stimulation (TMS) and sensory cortex excitability using somatosensory evoked potentials (SEPs) before and after 30 min of PES to right abductor pollicis brevis (APB). Two PES paradigms were tested in separate sessions; PES sufficient to induce a tetanic motor contraction (30–50 Hz; strong motor intensity) and PES at sub motor-threshold intensity (100 Hz). PES applied to induce strong activation of APB increased the size of the N20-P25 component, thought to reflect sensory processing at cortical level, and increased corticomotor excitability. PES at sensory intensity decreased the size of the P25-N33 component and reduced corticomotor excitability. A positive correlation was observed between the changes in amplitude of the cortical SEP components and corticomotor excitability following sensory and motor PES. Sensory PES also increased the sub-cortical P14-N20 SEP component. These findings provide evidence that PES results in co-modulation of S1 and M1 excitability, possibly due to cortico-cortical projections between S1 and M1. This mechanism may underpin changes in corticomotor excitability in response to afferent input generated by PES. PMID:23227260

  15. Axonal morphological changes following impulse activity in mouse peripheral nerve in vivo: the return pathway for sodium ions

    PubMed Central

    Trigo, Diogo; Smith, Kenneth J

    2015-01-01

    Myelinated axons can conduct sustained trains of impulses at high frequency, but this involves substantial ion movements that must be reversed to restore homeostasis. Little attention has been paid to the potential osmotic consequences of the ion movements or to the pathway taken by sodium ions returning to their original endoneurial location, given that the axolemmal Na+–K+-ATPase extrudes these ions into the periaxonal space beneath the myelin rather than into the endoneurium. Serial confocal imaging of fluorescent axons conducting at sustained physiological frequencies in vivo has revealed surprising morphological changes that may illuminate these problems. Saphenous nerves and spinal roots of anaesthetized transgenic mice expressing axoplasmic yellow fluorescent protein were stimulated electrically or pharmacologically (veratridine). Within 2 h, the axon herniated on one or both sides of the nodal membrane, displacing the paranodal myelin and widening the nodal gap. The herniated axoplasm became directed back towards the internode, forming a ‘cap’ up to 30 μm long. Concurrently, the fluid in the expanded periaxonal space accumulated into droplets that appeared to travel to the paranode, where they escaped. No such alterations occurred in axons treated with sodium channel or Na+–K+-ATPase inhibitors. Remarkably, impulse conduction continued throughout, and all these changes reversed spontaneously over hours or days. The morphological changes were verified ultrastructurally, and occurred in virtually all myelinated axons. The findings appear to reveal an overlooked part of the physiological repertoire of nerve fibres, and here they are interpreted in terms of osmotic changes that may illuminate the pathway by which sodium ions return to the endoneurial space after they have entered the axon during impulse conduction. PMID:25524071

  16. HDAC6 Inhibitors Rescued the Defective Axonal Mitochondrial Movement in Motor Neurons Derived from the Induced Pluripotent Stem Cells of Peripheral Neuropathy Patients with HSPB1 Mutation

    PubMed Central

    Hong, Young Bin; Choi, Heesun; Kim, Jisoo; Choi, Hyunjung; Mook-Jung, Inhee; Ha, Nina; Kyung, Jangbeen; Koo, Soo Kyung

    2016-01-01

    The Charcot-Marie-Tooth disease 2F (CMT2F) and distal hereditary motor neuropathy 2B (dHMN2B) are caused by autosomal dominantly inherited mutations of the heat shock 27 kDa protein 1 (HSPB1) gene and there are no specific therapies available yet. Here, we assessed the potential therapeutic effect of HDAC6 inhibitors on peripheral neuropathy with HSPB1 mutation using in vitro model of motor neurons derived from induced pluripotent stem cells (iPSCs) of CMT2F and dHMN2B patients. The absolute velocity of mitochondrial movements and the percentage of moving mitochondria in axons were lower both in CMT2F-motor neurons and in dHMN2B-motor neurons than those in controls, and the severity of the defective mitochondrial movement was different between the two disease models. CMT2F-motor neurons and dHMN2B-motor neurons also showed reduced α-tubulin acetylation compared with controls. The newly developed HDAC6 inhibitors, CHEMICAL X4 and CHEMICAL X9, increased acetylation of α-tubulin and reversed axonal movement defects of mitochondria in CMT2F-motor neurons and dHMN2B-motor neurons. Our results suggest that the neurons derived from patient-specific iPSCs can be used in drug screening including HDAC6 inhibitors targeting peripheral neuropathy. PMID:28105056

  17. HDAC6 Inhibitors Rescued the Defective Axonal Mitochondrial Movement in Motor Neurons Derived from the Induced Pluripotent Stem Cells of Peripheral Neuropathy Patients with HSPB1 Mutation.

    PubMed

    Kim, Ji-Yon; Woo, So-Youn; Hong, Young Bin; Choi, Heesun; Kim, Jisoo; Choi, Hyunjung; Mook-Jung, Inhee; Ha, Nina; Kyung, Jangbeen; Koo, Soo Kyung; Jung, Sung-Chul; Choi, Byung-Ok

    2016-01-01

    The Charcot-Marie-Tooth disease 2F (CMT2F) and distal hereditary motor neuropathy 2B (dHMN2B) are caused by autosomal dominantly inherited mutations of the heat shock 27 kDa protein 1 (HSPB1) gene and there are no specific therapies available yet. Here, we assessed the potential therapeutic effect of HDAC6 inhibitors on peripheral neuropathy with HSPB1 mutation using in vitro model of motor neurons derived from induced pluripotent stem cells (iPSCs) of CMT2F and dHMN2B patients. The absolute velocity of mitochondrial movements and the percentage of moving mitochondria in axons were lower both in CMT2F-motor neurons and in dHMN2B-motor neurons than those in controls, and the severity of the defective mitochondrial movement was different between the two disease models. CMT2F-motor neurons and dHMN2B-motor neurons also showed reduced α-tubulin acetylation compared with controls. The newly developed HDAC6 inhibitors, CHEMICAL X4 and CHEMICAL X9, increased acetylation of α-tubulin and reversed axonal movement defects of mitochondria in CMT2F-motor neurons and dHMN2B-motor neurons. Our results suggest that the neurons derived from patient-specific iPSCs can be used in drug screening including HDAC6 inhibitors targeting peripheral neuropathy.

  18. Poor efficacy of the phosphorylated high-molecular-weight neurofilament heavy subunit serum level, a biomarker of axonal damage, as a marker of chemotherapy-induced peripheral neuropathy.

    PubMed

    Sumitani, Masahiko; Ogata, Toru; Natori, Akina; Hozumi, Jun; Shimojo, Nobutake; Kida, Kumiko; Yamauchi, Hideko; Yamauchi, Teruo

    2016-06-01

    The phosphorylated form of the high-molecular-weight neurofilament heavy subunit (pNF-H) is a major structural protein in axons. The pNF-H level is elevated in the serum of certain patients with central nervous disorders, including chemotherapy-induced cognitive impairment. The present study was conducted to elucidate the potential role of pNF-H as a marker of chemotherapy-induced peripheral neuropathy (CIPN). A total of 71 patients with early breast cancer in various stages of treatment (following 1, 3 or 7 cycles of chemotherapy, or a previous history of breast cancer chemotherapy) were assessed with a self-administered PainDETECT questionnaire [pain location, pain intensity on an 11-point numeric rating scale (NRS), and various pain qualities] and a single serum pNF-H measurement. Patients were divided into two groups based on the presence or absence of bilateral symmetric pain in the distal portions of the extremities [CIPN(+) or CIPN(-)]. The χ(2) and Mann-Whitney tests were used for statistical analyses. Among the participants, only 8 patients complained of CIPN. Their pain intensity was 3.5±1.9 (mean ± standard deviation) compared with 1.5±1.8 in the CIPN(-) group (P<0.01). The NRS of numbness in the CIPN(+) group was significantly higher (2.4±1.4) than that of the CIPN(-) group (1.0±1.0). Increased pNF-H levels were observed in 37.5% of the CIPN(+) patients and in 23.8% of CIPN(-) patients (P=0.40). In conclusion, CIPN is observed in the most distal portions of the peripheral nerves that are composed of dendrites but not axons. Although serum pNF-H is a biomarker of axonal damage, it is not useful as a marker of CIPN.

  19. Neurofilament gene expression: a major determinant of axonal caliber

    SciTech Connect

    Hoffman, P.N.; Cleveland, D.W.; Griffin, J.W.; Landes, P.W.; Cowan, N.J.; Price, D.L.

    1987-05-01

    Within the wide spectrum of axonal diameters occurring in mammalian nerve fibers, each class of neurons has a relatively restricted range of axonal calibers. The control of caliber has functional significance because diameter is the principal determinant of conduction velocity in myelinated nerve fibers. Previous observations support the hypothesis that neurofilaments (NF) are major intrinsic determinants of axonal caliber in large myelinated nerve fibers. Following interruption of axons (axotomy) by crushing or cutting a peripheral nerve, caliber is reduced in the proximal axonal stumps, which extend from the cell bodies to the site of axotomy. This reduction in axonal caliber in the proximal stumps is associated with a selective diminution in the amount of NF protein undergoing slow axonal transport in these axons, with a decrease in axonal NF content, and with reduced conduction velocity. The present report demonstrates that changes in axonal caliber after axotomy correlate with a selective alteration in NF gene expression. Hybridization with specific cDNAs was used to measure levels of mRNA encoding the 68-kDa neurofilament protein (NF68), ..beta..-tubulin, and actin in lumbar sensory neurons of rat at various times after crushing the sciatic nerve. Between 4 and 42 days after axotomy by nerve crush, the levels of NF68 mRNA were reduced 2- to 3-fold. At the same times, the levels of tubulin and actin mRNAs were increased several-fold. These findings support the hypothesis that the expression of a single set of neuron-specific genes (encoding NF) directly determines axonal caliber, a feature neuronal morphology with important consequences for physiology and behavior.

  20. Neonatal sensory nerve injury-induced synaptic plasticity in the trigeminal principal sensory nucleus.

    PubMed

    Lo, Fu-Sun; Erzurumlu, Reha S

    2016-01-01

    Sensory deprivation studies in neonatal mammals, such as monocular eye closure, whisker trimming, and chemical blockade of the olfactory epithelium have revealed the importance of sensory inputs in brain wiring during distinct critical periods. But very few studies have paid attention to the effects of neonatal peripheral sensory nerve damage on synaptic wiring of the central nervous system (CNS) circuits. Peripheral somatosensory nerves differ from other special sensory afferents in that they are more prone to crush or severance because of their locations in the body. Unlike the visual and auditory afferents, these nerves show regenerative capabilities after damage. Uniquely, damage to a somatosensory peripheral nerve does not only block activity incoming from the sensory receptors but also mediates injury-induced neuro- and glial chemical signals to the brain through the uninjured central axons of the primary sensory neurons. These chemical signals can have both far more and longer lasting effects than sensory blockade alone. Here we review studies which focus on the consequences of neonatal peripheral sensory nerve damage in the principal sensory nucleus of the brainstem trigeminal complex.

  1. A locus for axonal motor-sensory neuropathy with deafness and mental retardation maps to Xq24-q26

    SciTech Connect

    Priest, J.M.; Nouri, N.; Keats, B.J.B.

    1995-09-20

    DNA markers on the X chromosome were used to map the locus for an unusual form of X-linked recessive hereditary motor and sensory neuropathy with associated deafness and mental retardation in a three-generation family that was originally reported by Towchock et al. This family included seven affected males, three obligate carrier females, and four unaffected males. The patients were severely affected within the first few years of life with distal weakness, muscle atrophy, sensory loss, areflexia, pes cavus, and hammer toes. Five of the seven affected males showed associated deafness, and three of these five individuals also presented with mental retardation or social development delay. Motor nerve conduction velocitites in affected males were normal to mildly delayed, and sensory conduction was markedly abnormal. Heterozygous females were asymptomatic. Close linkage to the Xg blood group locus (Xp22) and the PGK locus (Xq13) was previously excluded in this family, while weak linkage of the disease gene to DXYS1 (Xq21.3) was suggested. Our current linkage studies and haplotype analysis of 19 microsatellite markers on the long arm of the X chromosome demonstrate that DXS425 (Xq24) and HPRT (Xq26.1) are flanking markers and that the disease gene is closely linked to the markers DSX1122, DXS994, DXS737, DXS100, DXS1206, and DXS1047. 27 refs., 1 fig., 2 tabs.

  2. Axonal outgrowth on nano-imprinted patterns.

    PubMed

    Johansson, Fredrik; Carlberg, Patrick; Danielsen, Nils; Montelius, Lars; Kanje, Martin

    2006-03-01

    Nanotechnology has provided methods to fabricate surface patterns with features down to a few nm. If cells or cell processes exhibit contact guidance in response to such small patterns is an interesting question and could be pertinent for many applications. In the present study we investigated if axonal outgrowth was affected by nano-printed patterns in polymethylmethacrylate (PMMA)-covered silicon chips. To this end adult mouse sympathetic and sensory ganglia were mounted in Matrigel on the chips close to the nano-patterns. The patterns consisted of parallel grooves with depths of 300 nm and varying widths of 100-400 nm. The distance between two adjacent grooves was 100-1600 nm. The chips were cultured in medium containing 25 ng/ml of nerve growth factor to stimulate axonal outgrowth. After 1 week of incubation, axonal outgrowth was investigated by immunocytochemistry or scanning electron microscopy. Axons displayed contact guidance on all patterns. Furthermore, we found that the nerve cell processes preferred to grow on ridge edges and elevations in the patterns rather than in grooves, a seemingly claustrophobic behavior. We conclude that axons of peripheral neurons might be guided by nanopatterns on PMMA when the lateral features are 100 nm or larger. The present results can be utilized for nerve regenerating scaffolds or the construction of a stable, high-resolution electronic interface to neurons, which is required for future brain machine interfaces.

  3. Dynamic Changes in Local Protein Synthetic Machinery in Regenerating Central Nervous System Axons after Spinal Cord Injury.

    PubMed

    Sachdeva, Rahul; Farrell, Kaitlin; McMullen, Mary-Katharine; Twiss, Jeffery L; Houle, John D

    2016-01-01

    Intra-axonal localization of mRNAs and protein synthesis machinery (PSM) endows neurons with the capacity to generate proteins locally, allowing precise spatiotemporal regulation of the axonal response to extracellular stimuli. A number of studies suggest that this local translation is a promising target to enhance the regenerative capacity of damaged axons. Using a model of central nervous system (CNS) axons regenerating into intraspinal peripheral nerve grafts (PNGs) we established that adult regenerating CNS axons contain several different mRNAs and protein synthetic machinery (PSM) components in vivo. After lower thoracic level spinal cord transection, ascending sensory axons regenerate into intraspinal PNGs but axon growth is stalled when they reach the distal end of the PNG (3 versus 7 weeks after grafting, resp.). By immunofluorescence with optical sectioning of axons by confocal microscopy, the total and phosphorylated forms of PSMs are significantly lower in stalled compared with actively regenerating axons. Reinjury of these stalled axons increased axonal localization of the PSM proteins, indicative of possible priming for a subcellular response to axotomy. These results suggest that axons downregulate protein synthetic capacity as they cease growing, yet they retain the ability to upregulate PSM after a second injury.

  4. Dynamic Changes in Local Protein Synthetic Machinery in Regenerating Central Nervous System Axons after Spinal Cord Injury

    PubMed Central

    Sachdeva, Rahul; Farrell, Kaitlin; McMullen, Mary-Katharine; Twiss, Jeffery L.; Houle, John D.

    2016-01-01

    Intra-axonal localization of mRNAs and protein synthesis machinery (PSM) endows neurons with the capacity to generate proteins locally, allowing precise spatiotemporal regulation of the axonal response to extracellular stimuli. A number of studies suggest that this local translation is a promising target to enhance the regenerative capacity of damaged axons. Using a model of central nervous system (CNS) axons regenerating into intraspinal peripheral nerve grafts (PNGs) we established that adult regenerating CNS axons contain several different mRNAs and protein synthetic machinery (PSM) components in vivo. After lower thoracic level spinal cord transection, ascending sensory axons regenerate into intraspinal PNGs but axon growth is stalled when they reach the distal end of the PNG (3 versus 7 weeks after grafting, resp.). By immunofluorescence with optical sectioning of axons by confocal microscopy, the total and phosphorylated forms of PSMs are significantly lower in stalled compared with actively regenerating axons. Reinjury of these stalled axons increased axonal localization of the PSM proteins, indicative of possible priming for a subcellular response to axotomy. These results suggest that axons downregulate protein synthetic capacity as they cease growing, yet they retain the ability to upregulate PSM after a second injury. PMID:27375904

  5. Painful traumatic peripheral partial nerve injury-sensory dysfunction profiles comparing outcomes of bedside examination and quantitative sensory testing.

    PubMed

    Leffler, Ann-Sofie; Hansson, Per

    2008-05-01

    The primary aim of this retrospective study was to focusing on the relationship between individual outcomes of bedside examination (BE) and quantitative testing of somatosensory functions (QST) in 32 patients with painful traumatic partial nerve injury. In addition, the potential presence of common sensory dysfunction denominators has been probed. Patients with a history of traumatic partial nerve injury and ongoing pain were included if pain was confined to the entire or part of the innervation territory of the severed nerve and a bedside titration of the neuron-anatomical borders confirmed sensory aberrations. An in-depth BE and QST was then performed in the most painful area. Categorization of normal and pathological outcome for both BE and QST was based on time honoured clinical decision-making using the healthy contralateral corresponding area as control. In patients with normal outcome or quantitative aberrations (i.e. hypo- or hyperesthesia) at BE and QST, the same individual outcome of touch sensation was reported by 48% of the patients, for cold in 54% and for warmth in 58%. The most common dysfunction found at both BE and QST was hypoesthesia, however with no common denominators in somatosensory dysfunction. In conclusion, this study demonstrated that not infrequently the individual outcome of BE and the corresponding QST measure differed, most frequently for touch sensibility. This finding is of outmost importance when QST outcomes are used to corroborate results from BE in the diagnostic situation.

  6. Influence of Breaching the Connective Sheaths of the Donor Nerve on Its Myelinated Sensory Axons and on Their Sprouting into the End-to-Side Coapted Nerve in the Rat

    PubMed Central

    Žele, Tilen; Tomšič, Martin; Sketelj, Janez; Bajrović, Fajko F.

    2012-01-01

    Abstract The influence of breaching the connective sheaths of the donor sural nerve on axonal sprouting into the end-to-side coapted peroneal nerve was examined in the rat. In parallel, the effect of these procedures on the donor nerve was assessed. The sheaths of the donor nerve at the coaptation site were either left completely intact (group A) or they were breached by epineurial sutures (group B), an epineurial window (group C), or a perineurial window (group D). In group A, the compound action potential (CAP) of sensory axons was detected in ∼10% and 40% of the recipient nerves at 4 and 8 weeks, respectively, which was significantly less frequently than in group D at both recovery periods. In addition, the number of myelinated axons in the recipient nerve was significantly larger in group D than in other groups at 4 weeks. At 8 weeks, the number of axons in group A was only ∼15% of the axon numbers in other groups (p<0.05). Focal subepineurial degenerative changes in the donor nerves were only seen after 4 weeks, but not later. The average CAP area and the total number of myelinated axons in the donor nerves were not different among the experimental groups. In conclusion, myelinated sensory axons are able to penetrate the epiperineurium of donor nerves after end-to-side nerve coaption; however, their ingrowth into recipient nerves is significantly enhanced by breaching the epiperineurial sheets at the coaptation site. Breaching does not cause permanent injury to the donor nerve. PMID:22873667

  7. Fast-spiking GABA circuit dynamics in the auditory cortex predict recovery of sensory processing following peripheral nerve damage

    PubMed Central

    Resnik, Jennifer; Polley, Daniel B

    2017-01-01

    Cortical neurons remap their receptive fields and rescale sensitivity to spared peripheral inputs following sensory nerve damage. To address how these plasticity processes are coordinated over the course of functional recovery, we tracked receptive field reorganization, spontaneous activity, and response gain from individual principal neurons in the adult mouse auditory cortex over a 50-day period surrounding either moderate or massive auditory nerve damage. We related the day-by-day recovery of sound processing to dynamic changes in the strength of intracortical inhibition from parvalbumin-expressing (PV) inhibitory neurons. Whereas the status of brainstem-evoked potentials did not predict the recovery of sensory responses to surviving nerve fibers, homeostatic adjustments in PV-mediated inhibition during the first days following injury could predict the eventual recovery of cortical sound processing weeks later. These findings underscore the potential importance of self-regulated inhibitory dynamics for the restoration of sensory processing in excitatory neurons following peripheral nerve injuries. DOI: http://dx.doi.org/10.7554/eLife.21452.001 PMID:28323619

  8. Characterisation of cannabinoid 1 receptor expression in the perikarya, and peripheral and spinal processes of primary sensory neurons.

    PubMed

    Veress, Gabor; Meszar, Zoltan; Muszil, Dora; Avelino, Antonio; Matesz, Klara; Mackie, Ken; Nagy, Istvan

    2013-05-01

    The cannabinoid 1 (CB1) receptor is expressed by a sub-population of primary sensory neurons. However, data on the neurochemical identity of the CB1 receptor-expressing cells, and CB1 receptor expression by the peripheral and central terminals of these neurons are inconsistent and limited. We characterised CB1 receptor expression in dorsal root ganglia (DRG) and spinal cord at the lumbar 4-5 level, as well as in the urinary bladder and glabrous skin of the hindpaw. About 1/3 of DRG neurons exhibited immunopositivity for the CB1 receptor, the majority of which showed positivity for the nociceptive markers calcitonin gene-related peptide (CGRP) or/and Griffonia (bandeiraea) simplicifolia IB4 isolectin-binding. Virtually all CB1 receptor-immunostained fibres showed immunopositivity for CGRP in the skin, while very few did in the urinary bladder. No CB1 receptor-immunopositive nerve fibres were IB4 positive in either peripheral tissue. Spinal laminae I and II-outer showed the highest density of CB1 receptor-immunopositive punctae, the majority of which showed positivity for CGRP or/and IB4 binding. These data indicate that a major sub-population of nociceptive primary sensory neurons expresses CB1 receptors that are transported to both peripheral and central terminals of these cells. Therefore, the present data suggest that manipulation of endogenous CB1 receptor agonist levels in these areas may significantly reduce nociceptive input into the spinal cord.

  9. Critical role of peripheral sensory systems in mediating the neural effects of nicotine following its acute and repeated exposure

    PubMed Central

    Kiyatkin, Eugene A.

    2015-01-01

    It is well established that the reinforcing properties of nicotine depend upon its action on nicotinic acetylcholine receptors expressed by brain neurons. However, when administered systemically, nicotine first phasically activates nicotinic receptors located on the afferents of sensory nerves at the sites of drug administration before reaching the brain and directly interacting with central neurons. While this peripheral action of nicotine has been known for years, it is usually neglected in any consideration of the drug’s reinforcing properties and experience-dependent changes of its behavioral and physiological effects. The goal of this work is to review our recent behavioral, electrophysiological, and physiological data, suggesting the critical importance of peripheral actions of nicotine in mediating its neural effects following acute drug exposure and their involvement in alterations of NIC effects consistently occurring following repeated drug exposure. Since nicotine by acting peripherally produces a rapid sensory signal to the CNS that is followed by slower, more prolonged direct drug actions in the brain, these two pharmacological actions interact in the CNS during repeated drug use with the development of Pavlovian conditioned association. This within-drug conditioning mechanism could explain experience-dependent changes in the physiological, behavioral, and human psycho-emotional effects of nicotine, which in drug-experienced individuals always represent a combination of pharmacological and learning variables. PMID:24535300

  10. The Dyslexia-susceptibility Protein KIAA0319 Inhibits Axon Growth Through Smad2 Signaling.

    PubMed

    Franquinho, Filipa; Nogueira-Rodrigues, Joana; Duarte, Joana M; Esteves, Sofia S; Carter-Su, Christin; Monaco, Anthony P; Molnár, Zoltán; Velayos-Baeza, Antonio; Brites, Pedro; Sousa, Mónica M

    2017-03-01

    KIAA0319 is a transmembrane protein associated with dyslexia with a presumed role in neuronal migration. Here we show that KIAA0319 expression is not restricted to the brain but also occurs in sensory and spinal cord neurons, increasing from early postnatal stages to adulthood and being downregulated by injury. This suggested that KIAA0319 participates in functions unrelated to neuronal migration. Supporting this hypothesis, overexpression of KIAA0319 repressed axon growth in hippocampal and dorsal root ganglia neurons; the intracellular domain of KIAA0319 was sufficient to elicit this effect. A similar inhibitory effect was observed in vivo as axon regeneration was impaired after transduction of sensory neurons with KIAA0319. Conversely, the deletion of Kiaa0319 in neurons increased neurite outgrowth in vitro and improved axon regeneration in vivo. At the mechanistic level, KIAA0319 engaged the JAK2-SH2B1 pathway to activate Smad2, which played a central role in KIAA0319-mediated repression of axon growth. In summary, we establish KIAA0319 as a novel player in axon growth and regeneration with the ability to repress the intrinsic growth potential of axons. This study describes a novel regulatory mechanism operating during peripheral nervous system and central nervous system axon growth, and offers novel targets for the development of effective therapies to promote axon regeneration. © The Author 2017. Published by Oxford University Press.

  11. Sensory Functions, Balance, and Mobility in Older Adults With Type 2 Diabetes Without Overt Diabetic Peripheral Neuropathy: A Brief Report.

    PubMed

    Deshpande, Nandini; Hewston, Patricia; Aldred, Alison

    2015-08-30

    This study examined possible subtle degradation in sensory functions, balance, and mobility in older adults with type 2 diabetes (T2D) prior to overt development of diabetic peripheral neuropathy (DPN). Twenty-five healthy controls (HC group, age = 74.6 ± 5.4) and 35 T2D elderly without DPN (T2D group, age = 70.6 ± 4.7) were recruited. Sensory assessment included vibrotactile sensitivity, bilateral caloric weakness, and visual contrast sensitivity. Self-report measures comprised of Activity-Specific Balance Confidence (ABC), Human Activity Profile-adjusted activity scores (HAP-AAS), falls, and mobility disability. Performance measures included modified Timed-Up and Go (mTUG), Clinical Test of Sensory Integration for Balance (mCTSIB), and Frailty and Injuries (FICSIT-4) balance test. T2D group demonstrated significantly worse bilateral caloric weakness, marginally higher threshold of vibrotactile sensitivity and lower visual contrast sensitivity, and as well as signifcantly lower HAP-AAS. A significantly higher proportion of the T2D group failed mCTSIB Condition 4 than in the HC group. Subtle changes in multiple sensory systems of older adults with T2D may reduce redundancy available for balance control while performing challenging activities much before DPN development. © The Author(s) 2015.

  12. Sensory, psychological, and metabolic dysfunction in HIV-associated peripheral neuropathy: A cross-sectional deep profiling study.

    PubMed

    Phillips, Tudor J C; Brown, Matthew; Ramirez, Juan D; Perkins, James; Woldeamanuel, Yohannes W; Williams, Amanda C de C; Orengo, Christine; Bennett, David L H; Bodi, Istvan; Cox, Sarah; Maier, Christoph; Krumova, Elena K; Rice, Andrew S C

    2014-09-01

    HIV-associated sensory neuropathy (HIV-SN) is a frequent complication of HIV infection and a major source of morbidity. A cross-sectional deep profiling study examining HIV-SN was conducted in people living with HIV in a high resource setting using a battery of measures which included the following: parameters of pain and sensory symptoms (7day pain diary, Neuropathic Pain Symptom Inventory [NPSI] and Brief Pain Inventory [BPI]), sensory innervation (structured neurological examination, quantitative sensory testing [QST] and intraepidermal nerve fibre density [IENFD]), psychological state (Pain Anxiety Symptoms Scale-20 [PASS-20], Depression Anxiety and Positive Outlook Scale [DAPOS], and Pain Catastrophizing Scale [PCS], insomnia (Insomnia Severity Index [ISI]), and quality of life (Short Form (36) Health Survey [SF-36]). The diagnostic utility of the Brief Peripheral Neuropathy Screen (BPNS), Utah Early Neuropathy Scale (UENS), and Toronto Clinical Scoring System (TCSS) were evaluated. Thirty-six healthy volunteers and 66 HIV infected participants were recruited. A novel triumvirate case definition for HIV-SN was used that required 2 out of 3 of the following: 2 or more abnormal QST findings, reduced IENFD, and signs of a peripheral neuropathy on a structured neurological examination. Of those with HIV, 42% fulfilled the case definition for HIV-SN (n=28), of whom 75% (n=21) reported pain. The most frequent QST abnormalities in HIV-SN were loss of function in mechanical and vibration detection. Structured clinical examination was superior to QST or IENFD in HIV-SN diagnosis. HIV-SN participants had higher plasma triglyceride, concentrations depression, anxiety and catastrophizing scores, and prevalence of insomnia than HIV participants without HIV-SN.

  13. Sensory, psychological, and metabolic dysfunction in HIV-associated peripheral neuropathy: A cross-sectional deep profiling study

    PubMed Central

    Phillips, Tudor J.C.; Brown, Matthew; Ramirez, Juan D.; Perkins, James; Woldeamanuel, Yohannes W.; Williams, Amanda C. de C.; Orengo, Christine; Bennett, David L.H.; Bodi, Istvan; Cox, Sarah; Maier, Christoph; Krumova, Elena K.; Rice, Andrew S.C.

    2014-01-01

    HIV-associated sensory neuropathy (HIV-SN) is a frequent complication of HIV infection and a major source of morbidity. A cross-sectional deep profiling study examining HIV-SN was conducted in people living with HIV in a high resource setting using a battery of measures which included the following: parameters of pain and sensory symptoms (7 day pain diary, Neuropathic Pain Symptom Inventory [NPSI] and Brief Pain Inventory [BPI]), sensory innervation (structured neurological examination, quantitative sensory testing [QST] and intraepidermal nerve fibre density [IENFD]), psychological state (Pain Anxiety Symptoms Scale-20 [PASS-20], Depression Anxiety and Positive Outlook Scale [DAPOS], and Pain Catastrophizing Scale [PCS], insomnia (Insomnia Severity Index [ISI]), and quality of life (Short Form (36) Health Survey [SF-36]). The diagnostic utility of the Brief Peripheral Neuropathy Screen (BPNS), Utah Early Neuropathy Scale (UENS), and Toronto Clinical Scoring System (TCSS) were evaluated. Thirty-six healthy volunteers and 66 HIV infected participants were recruited. A novel triumvirate case definition for HIV-SN was used that required 2 out of 3 of the following: 2 or more abnormal QST findings, reduced IENFD, and signs of a peripheral neuropathy on a structured neurological examination. Of those with HIV, 42% fulfilled the case definition for HIV-SN (n = 28), of whom 75% (n = 21) reported pain. The most frequent QST abnormalities in HIV-SN were loss of function in mechanical and vibration detection. Structured clinical examination was superior to QST or IENFD in HIV-SN diagnosis. HIV-SN participants had higher plasma triglyceride, concentrations depression, anxiety and catastrophizing scores, and prevalence of insomnia than HIV participants without HIV-SN. PMID:24973717

  14. Lox6, a leech Dfd ortholog, is expressed in the central nervous system and in peripheral sensory structures.

    PubMed

    Wong, V Y; Macagno, E R

    1998-03-01

    Sequence analysis of a newly isolated Hirudo medicinalis cDNA containing an Antennapedia (Antp)-class homeobox suggests that the corresponding gene, Lox6, is an ortholog of the Drosophila Deformed (Dfd) gene. In situ hybridization of whole-mounted preparations shows that the major sites of Lox6 expression during embryogenesis are the central nervous system (CNS) and the peripheral sensory system. Lox6 mRNA can be detected in a subset of neurons in each ganglion from the subesophageal ganglion (RG2) to the most posterior ganglion, with the highest level of expression seen in RG3. Peripherally, Lox6 is expressed principally in the primordia of the sensillae and in the eyes. This pattern of expression of Lox6 suggests that one of its functions may be to contribute to the diversification of neuronal phenotypes.

  15. Cross-Excitation in Peripheral Sensory Ganglia Associated with Pain Transmission

    PubMed Central

    Omoto, Katsuhiro; Maruhama, Kotaro; Terayama, Ryuji; Yamamoto, Yumiko; Matsushita, Osamu; Sugimoto, Tomosada; Oguma, Keiji; Matsuka, Yoshizo

    2015-01-01

    Despite the absence of synaptic contacts, cross-excitation of neurons in sensory ganglia during signal transmission is considered to be chemically mediated and appears increased in chronic pain states. In this study, we modulated neurotransmitter release in sensory neurons by direct application of type A botulinum neurotoxin (BoNT/A) to sensory ganglia in an animal model of neuropathic pain and evaluated the effect of this treatment on nocifensive. Unilateral sciatic nerve entrapment (SNE) reduced the ipsilateral hindpaw withdrawal threshold to mechanical stimulation and reduced hindpaw withdrawal latency to thermal stimulation. Direct application of BoNT/A to the ipsilateral L4 dorsal root ganglion (DRG) was localized in the cell bodies of the DRG and reversed the SNE-induced decreases in withdrawal thresholds within 2 days of BoNT/A administration. Results from this study suggest that neurotransmitter release within sensory ganglia is involved in the regulation of pain-related signal transmission. PMID:26248078

  16. Cross-Excitation in Peripheral Sensory Ganglia Associated with Pain Transmission.

    PubMed

    Omoto, Katsuhiro; Maruhama, Kotaro; Terayama, Ryuji; Yamamoto, Yumiko; Matsushita, Osamu; Sugimoto, Tomosada; Oguma, Keiji; Matsuka, Yoshizo

    2015-08-04

    Despite the absence of synaptic contacts, cross-excitation of neurons in sensory ganglia during signal transmission is considered to be chemically mediated and appears increased in chronic pain states. In this study, we modulated neurotransmitter release in sensory neurons by direct application of type A botulinum neurotoxin (BoNT/A) to sensory ganglia in an animal model of neuropathic pain and evaluated the effect of this treatment on nocifensive. Unilateral sciatic nerve entrapment (SNE) reduced the ipsilateral hindpaw withdrawal threshold to mechanical stimulation and reduced hindpaw withdrawal latency to thermal stimulation. Direct application of BoNT/A to the ipsilateral L4 dorsal root ganglion (DRG) was localized in the cell bodies of the DRG and reversed the SNE-induced decreases in withdrawal thresholds within 2 days of BoNT/A administration. Results from this study suggest that neurotransmitter release within sensory ganglia is involved in the regulation of pain-related signal transmission.

  17. The leukotriene B4 receptors BLT1 and BLT2 form an antagonistic sensitizing system in peripheral sensory neurons.

    PubMed

    Zinn, Sebastian; Sisignano, Marco; Kern, Katharina; Pierre, Sandra; Tunaru, Sorin; Jordan, Holger; Suo, Jing; Treutlein, Elsa-Marie; Angioni, Carlo; Ferreiros, Nerea; Leffler, Andreas; DeBruin, Natasja; Offermanns, Stefan; Geisslinger, Gerd; Scholich, Klaus

    2017-04-14

    Sensitization of the heat-activated ion channel transient receptor potential vanilloid 1 (TRPV1) through lipids is a fundamental mechanism during inflammation-induced peripheral sensitization. Leukotriene B4 is a proinflammatory lipid mediator whose role in peripheral nociceptive sensitization is not well understood to date. Two major G-protein-coupled receptors for leukotriene B4 have been identified: the high-affinity receptor BLT1 and the low-affinity receptor BLT2. Transcriptional screening for the expression G-protein-coupled receptors in murine dorsal root ganglia showed that both receptors were among the highest expressed in dorsal root ganglia. Calcium imaging revealed a sensitization of TRPV1-mediated calcium increases in a relative narrow concentration range for leukotriene B4 (100-200 nm). Selective antagonists and neurons from knock-out mice demonstrated a BLT1-dependent sensitization of TRPV1-mediated calcium increases. Accordingly, leukotriene B4-induced thermal hyperalgesia was mediated through BLT1 and TRPV1 as shown using the respective knock-out mice. Importantly, higher leukotriene B4 concentrations (>0.5 μm) and BLT2 agonists abolished sensitization of the TRPV1-mediated calcium increases. Also, BLT2 activation inhibited protein kinase C- and protein kinase A-mediated sensitization processes through the phosphatase calcineurin. Consequently, a selective BLT2-receptor agonist increased thermal and mechanical withdrawal thresholds during zymosan-induced inflammation. In accordance with these data, immunohistochemical analysis showed that both leukotriene B4 receptors were expressed in peripheral sensory neurons. Thus, the data show that the two leukotriene B4 receptors have opposing roles in the sensitization of peripheral sensory neurons forming a self-restricting system.

  18. Transforming Growth Factor-β Promotes Axonal Regeneration After Chronic Nerve Injury.

    PubMed

    Sulaiman, Wale A R

    2016-04-01

    When spinal cord injury (SCI) occurs, injured cells must survive and regenerate to close gaps caused by the injury and to create functional motor units. After peripheral nerve injury, Wallerian degeneration in the distal nerve stump creates a neurotrophic and growth-supportive environment for injured neurons and axons via Schwann cells and secreted cytokines/neurotrophins. In both SCI and peripheral nerve injury, injured motor and sensory neurons must regenerate axons, eventually reaching and reinnervating target tissue (SDC Figure 1, http://links.lww.com/BRS/B116). This process is often unsuccessful after SCI, and the highly complex anatomy of branching axons and nerves in the peripheral nervous system leads to slow recovery of function, even with careful and appropriate techniques.

  19. Peripherin Is a Subunit of Peripheral Nerve Neurofilaments: Implications for Differential Vulnerability of CNS and PNS Axons

    PubMed Central

    Yuan, Aidong; Sasaki, Takahiro; Kumar, Asok; Peterhoff, Corrinne M.; Rao, Mala V.; Liem, Ronald K.; Julien, Jean-Pierre; Nixon, Ralph A.

    2012-01-01

    Peripherin, a neuronal intermediate filament protein implicated in neurodegenerative disease, coexists with the neurofilament triplet proteins (NFL, NFM, and NFH) but has an unknown function. The earlier peak expression of peripherin than the triplet during brain development and its ability to form homopolymers, unlike the triplet, which are obligate heteropolymers, have supported a widely held view that peripherin and neurofilament triplet form separate filament systems. Here, we demonstrate, however, that despite a postnatal decline in expression, peripherin is as abundant as the triplet in the adult PNS and exists in a relatively fixed stoichiometry with these subunits. Peripherin exhibits a distribution pattern identical to those of triplet proteins in sciatic axons and co-localizes with NFL on single neurofilament by immunogold electron microscopy. Peripherin also co-assembles into a single network of filaments containing NFL, NFM, NFH with and without α-internexin in quadruple- or quintuple-transfected SW13 vim (−) cells. Genetically deleting NFL in mice dramatically reduces peripherin content in sciatic axons. Moreover, peripherin mutations has been shown to disrupt the neurofilament network in transfected SW13 vim(−) cells. These data show that peripherin and the neurofilament proteins are functionally interdependent. The results strongly support the view that rather than forming an independent structure, peripherin is a subunit of neurofilaments in the adult PNS. Our findings provide a basis for its close relationship with neurofilaments in PNS diseases associated with neurofilament accumulation. PMID:22723690

  20. Results of Arthroscopic Repair of Peripheral Triangular Fibrocartilage Complex Tear With Exploration of Dorsal Sensory Branch of Ulnar Nerve

    PubMed Central

    Chen, Alvin Chao-Yu; Weng, Chun-Jui; Chiu, Chih-Hao; Chang, Shih-Sheng; Cheng, Chun-Ying; Chan, Yi-Sheng

    2017-01-01

    Background: Ulnar-sided approach in arthroscopic triangular fibrocartilage complex (TFCC) repair may jeopardize treatment success by exposing the dorsal sensory branch of ulnar nerve (DSBUN) in risk of injury. We aim to conduct a follow-up assessment of arthroscopic outside-in TFCC repair and efficacy of sensory nerve exploration. Methods: We conducted a retrospective chart review of 58 patients (59 wrists) who received arthroscopic repair of the peripheral attachment of the TFCC. Ulnar-sided skin incision and exploration of DSBUN were performed before arthroscopy setting. Arthroscopic outside-in repair through pullout suture ligation was performed. Functional survey at 6 months and 1 year postoperatively was based on Mayo Modified Wrist Score (MMWS), and compared to the preoperative assessment. A p-value of less than 0.05 was considered significant as calculated using paired t-test. Results: Postoperative MMWS averaged 74.32±11.50 at 6 months, and 84.41±9.52 at one year; both showed significant difference as compared to preoperative status. Significant improvement was noted in all 4 individual items except motion retrieval between 6 months and 1 year. Totally, 45 (76%) cases achieved good or excellent results at one year; however, less patients resumed pre-injury activity level when treatment delay was more than 6 months than those treated earlier (41% vs. 57%). Complication included 6 transient paresthesia; 1 anchor migration and 1 distal radioulnar arthrosis. No more nerve complication was found after modification of perineural dissection. Conclusion: Arthroscopy is effective in obtaining both correct diagnosis and treatment of peripheral TFCC tear. Modified perineural dissection can minimize sensory nerve complications. PMID:28694892

  1. Netrin 1 and Dcc signalling are required for confinement of central axons within the central nervous system.

    PubMed

    Laumonnerie, Christophe; Da Silva, Ronan V; Kania, Artur; Wilson, Sara I

    2014-02-01

    The establishment of anatomically stereotyped axonal projections is fundamental to neuronal function. While most neurons project their axons within the central nervous system (CNS), only axons of centrally born motoneurons and peripherally born sensory neurons link the CNS and peripheral nervous system (PNS) together by navigating through specialized CNS/PNS transition zones. Such selective restriction is of importance because inappropriate CNS axonal exit could lead to loss of correct connectivity and also to gain of erroneous functions. However, to date, surprisingly little is known about the molecular-genetic mechanisms that regulate how central axons are confined within the CNS during development. Here, we show that netrin 1/Dcc/Unc5 chemotropism contributes to axonal confinement within the CNS. In both Ntn1 and Dcc mutant mouse embryos, some spinal interneuronal axons exit the CNS by traversing the CNS/PNS transition zones normally reserved for motor and sensory axons. We provide evidence that netrin 1 signalling preserves CNS/PNS axonal integrity in three ways: (1) netrin 1/Dcc ventral attraction diverts axons away from potential exit points; (2) a Dcc/Unc5c-dependent netrin 1 chemoinhibitory barrier in the dorsolateral spinal cord prevents interneurons from being close to the dorsal CNS/PNS transition zone; and (3) a netrin 1/Dcc-dependent, Unc5c-independent mechanism that actively prevents exit from the CNS. Together, these findings provide insights into the molecular mechanisms that maintain CNS/PNS integrity and, to the best of our knowledge, present the first evidence that chemotropic signalling regulates interneuronal CNS axonal confinement in vertebrates.

  2. The ErbB2 inhibitor Herceptin (Trastuzumab) promotes axonal outgrowth four weeks after acute nerve transection and repair.

    PubMed

    Placheta, Eva; Hendry, J Michael; Wood, Matthew D; Lafontaine, Christine W; Liu, Edward H; Cecilia Alvarez Veronesi, M; Frey, Manfred; Gordon, Tessa; Borschel, Gregory H

    2014-10-17

    Accumulating evidence suggests that neuregulin, a potent Schwann cell mitogen, and its receptor, ErbB2, have an important role in regulating peripheral nerve regeneration. We hypothesized that Herceptin (Trastuzumab), a monoclonal antibody that binds ErbB2, would disrupt ErbB2 signaling, allowing us to evaluate ErbB2's importance in peripheral nerve regeneration. In this study, the extent of peripheral motor and sensory nerve regeneration and distal axonal outgrowth was analyzed two and four weeks after common peroneal (CP) nerve injury in rats. Outcomes analyzed included neuron counts after retrograde labeling, histomorphometry, and protein analysis. The data analysis revealed that there was no impact of Herceptin administration on either the numbers of motor or sensory neurons that regenerated their axons but histomorphometry revealed that Herceptin significantly increased the number of regenerated axons in the distal repaired nerve after 4 weeks. Protein analysis with Western blotting revealed no difference in either expression levels of ErbB2 or the amount of activated, phosphorylated ErbB2 in injured nerves. In conclusion, administration of the ErbB2 receptor inhibitor after nerve transection and surgical repair did not alter the number of regenerating neurons but markedly increased the number of regenerated axons per neuron in the distal nerve stump. Enhanced axon outgrowth in the presence of this ErbB2 inhibitor indicates that ErbB2 signaling may limit the numbers of axons that are emitted from each regenerating neuron.

  3. Acrolein contributes to TRPA1 up-regulation in peripheral and central sensory hypersensitivity following spinal cord injury.

    PubMed

    Park, Jonghyuck; Zheng, Lingxing; Acosta, Glen; Vega-Alvarez, Sasha; Chen, Zhe; Muratori, Breanne; Cao, Peng; Shi, Riyi

    2015-12-01

    Acrolein, an endogenous aldehyde, has been shown to be involved in sensory hypersensitivity after rat spinal cord injury (SCI), for which the pathogenesis is unclear. Acrolein can directly activate a pro-algesic transient receptor protein ankyrin 1 (TRPA1) channel that exists in sensory neurons. Both acrolein and TRPA1 mRNA are elevated post SCI, which contributes to the activation of TRPA1 by acrolein and consequently, neuropathic pain. In the current study, we further showed that, post-SCI elevation of TRPA1 mRNA exists not only in dorsal root ganglias but also in both peripheral (paw skin) and central endings of primary afferent nerves (dorsal horn of spinal cord). This is the first indication that pain signaling can be over-amplified in the peripheral skin by elevated expressions of TRPA1 following SCI, in addition over-amplification previously seen in the spinal cord and dorsal root ganglia. Furthermore, we show that acrolein alone, in the absence of physical trauma, could lead to the elevation of TRPA1 mRNA at various locations when injected to the spinal cord. In addition, post-SCI elevation of TRPA1 mRNA could be mitigated using acrolein scavengers. Both of these attributes support the critical role of acrolein in elevating TRPA1 expression through gene regulation. Taken together, these data indicate that acrolein is likely a critical causal factor in heightening pain sensation post-SCI, through both the direct binding of TRPA1 receptor, and also by boosting the expression of TRPA1. Finally, our data also further support the notion that acrolein scavenging may be an effective therapeutic approach to alleviate neuropathic pain after SCI. We propose that the trauma-mediated elevation of acrolein causes neuropathic pain through at least two mechanisms: acrolein stimulates the production of transient receptor protein ankyrin 1 (TRPA1) in both central and peripheral locations, and it activates TRPA1 channels directly. Therefore, acrolein appears to be a critical

  4. Effects of peripherally and centrally acting analgesics on somato-sensory evoked potentials.

    PubMed Central

    Moore, U J; Marsh, V R; Ashton, C H; Seymour, R A

    1995-01-01

    1. The effects of aspirin 1000 mg, paracetamol 1000 mg, codeine 60 mg on somatosensory evoked potentials (SEPs) were measured in a four-way cross-over study. 2. SEPs were elicited by electrical stimulation of the skin overlying the digital nerve at intensities close to pain threshold. 3. Amplitudes and latencies of both early and late SEPs were recorded, as well as first sensory threshold and subjective pain threshold. 4. None of the study medications affected the amplitude or latency of the late SEP components (100-250 ms post-stimulus). The amplitude of early components (15-30 ms post-stimulus) was also unaffected, but aspirin shortened the latency 30 min after ingestion. 5. Sensory detection and pain threshold to electrical skin stimulation were also unaffected by any of the study medications despite subjective central effects with codeine. PMID:8562292

  5. A Functional Role for VEGFR1 Expressed in Peripheral Sensory Neurons in Cancer Pain

    PubMed Central

    Selvaraj, Deepitha; Gangadharan, Vijayan; Michalski, Christoph W.; Kurejova, Martina; Stösser, Sebastian; Srivastava, Kshitij; Schweizerhof, Matthias; Waltenberger, Johannes; Ferrara, Napoleone; Heppenstall, Paul; Shibuya, Masabumi; Augustin, Hellmut G.; Kuner, Rohini

    2015-01-01

    Summary Cancer pain is a debilitating disorder and a primary determinant of the poor quality of life. Here, we report a non-vascular role for ligands of the Vascular Endothelial Growth Factor (VEGF) family in cancer pain. Tumor-derived VEGF-A, PLGF-2, and VEGF-B augment pain sensitivity through selective activation of VEGF receptor 1 (VEGFR1) expressed in sensory neurons in human cancer and mouse models. Sensory-neuron-specific genetic deletion/silencing or local or systemic blockade of VEGFR1 prevented tumor-induced nerve remodeling and attenuated cancer pain in diverse mouse models in vivo. These findings identify a therapeutic potential for VEGFR1-modifying drugs in cancer pain and suggest a palliative effect for VEGF/VEGFR1-targeting anti-angiogenic tumor therapies. PMID:26058077

  6. Peripheral sensory neuron injury contributes to neuropathic pain in experimental autoimmune encephalomyelitis

    PubMed Central

    Wang, I-Ching; Chung, Chen-Yen; Liao, Fang; Chen, Chih-Cheng; Lee, Cheng-Han

    2017-01-01

    Multiple sclerosis (MS)-induced neuropathic pain deteriorates quality of life in patients but is often refractory to treatment. In experimental autoimmune encephalomyelitis (EAE), a rodent model of MS, animals develop neuropathy and inflammation-induced tissue acidosis, which suggests the involvement of acid-sensing ion channels (ASICs). Also, peripheral neuropathy is reported in MS patients. However, the involvement of the peripheral nervous system (PNS) in MS neuropathic pain remains elusive. This study investigated the contribution of ASICs and peripheral neuropathy in MS-induced neuropathic pain. Elicited pain levels were as high in Asic1a−/−, Asic2−/− and Asic3−/− mice as wild-type mice even though only Asic1a−/− mice showed reduced EAE disease severity, which indicates that pain in EAE was independent of disease severity. We thus adopted an EAE model without pertussis toxin (EAEnp) to restrain activated immunity in the periphery and evaluate the PNS contribution to pain. Both EAE and EAEnp mice showed similar pain behaviors and peripheral neuropathy in nerve fibers and DRG neurons. Moreover, pregabalin significantly reduced neuropathic pain in both EAE and EAEnp mice. Our findings highlight the essential role of the PNS in neuropathic pain in EAE and pave the way for future development of analgesics without side effects in the CNS. PMID:28181561

  7. Peripheral prostaglandin E2 prolongs the sensitization of nociceptive dorsal root ganglion neurons possibly by facilitating the synthesis and anterograde axonal trafficking of EP4 receptors.

    PubMed

    St-Jacques, Bruno; Ma, Weiya

    2014-11-01

    Prostaglandin E2 (PGE2), a well-known pain mediator enriched in inflamed tissues, plays a pivotal role in the genesis of chronic pain conditions such as inflammatory and neuropathic pain. PGE2-prolonged sensitization of nociceptive dorsal root ganglion (DRG) neurons (nociceptors) may contribute to the transition from acute to chronic pain. However, the underlying cellular mechanisms are poorly understood. In this study, we tested the hypothesis that facilitating synthesis and anterograde axonal trafficking of EP receptors contribute to PGE2-prolonged nociceptor sensitization. Intraplantar (i.pl.) injection of a stabilized PGE2 analog, 16,16 dimethyl PGE2 (dmPGE2), in a dose- and time-dependent manner, not only elicited primary tactile allodynia which lasted for 1d, but also prolonged tactile allodynia evoked by a subsequent i.pl. injection of dmPGE2 from 1d to 4d. Moreover, the duration of tactile allodynia was progressively prolonged following multiple sequential i.pl. injections of dmPGE2. Co-injection of the selective EP1 or EP4 receptor antagonist, the inhibitors of cAMP, PKA, PKC, PKCε or PLC as well as an interleukin-6 (IL-6) neutralizing antiserum differentially blocked primary tactile allodynia elicited by the 1st dmPGE2 and the prolonged tactile allodynia evoked by the 2nd dmPGE2, suggesting the involvement of these signaling events in dmPGE2-induced nociceptor activation and sensitization. Co-injection of a selective COX2 inhibitor or two EP4 antagonists prevented or shortened inflammagen-prolonged nociceptor sensitization. I.pl. injection of dmPGE2 or carrageenan time-dependently increased EP4 levels in L4-6 DRG neurons and peripheral nerves. EP4 was expressed in almost half of IB4-binding nociceptors of L4-6 DRG. Taken together, our data suggest that stimulating the synthesis and anterograde axonal trafficking to increase EP4 availability at the axonal terminals of nociceptors is likely a novel mechanism underlying PGE2-prolonged nociceptor

  8. Alpha-synuclein pathology and axonal degeneration of the peripheral motor nerves innervating pharyngeal muscles in Parkinson disease.

    PubMed

    Mu, Liancai; Sobotka, Stanislaw; Chen, Jingming; Su, Hungxi; Sanders, Ira; Adler, Charles H; Shill, Holly A; Caviness, John N; Samanta, Johan E; Beach, Thomas G

    2013-02-01

    Parkinson disease (PD) is a neurodegenerative disease primarily characterized by cardinal motor manifestations and CNS pathology. Current drug therapies can often stabilize these cardinal motor symptoms, and attention has shifted to the other motor and nonmotor symptoms of PD that are resistant to drug therapy. Dysphagia in PD is perhaps the most important drug-resistant symptom because it leads to aspiration and pneumonia, the leading cause of death. Here, we present direct evidence for degeneration of the pharyngeal motor nerves in PD. We examined the cervical vagal nerve (cranial nerve X), pharyngeal branch of nerve X, and pharyngeal plexus innervating the pharyngeal muscles in 14 postmortem specimens, that is, from 10 patients with PD and 4 age-matched control subjects. Synucleinopathy in the pharyngeal nerves was detected using an immunohistochemical method for phosphorylated α-synuclein. Alpha-synuclein aggregates were revealed in nerve X and the pharyngeal branch of nerve X, and immunoreactive intramuscular nerve twigs and axon terminals within the neuromuscular junctions were identified in all of the PD patients but in none of the controls. These findings indicate that the motor nervous system of the pharynx is involved in the pathologic process of PD. Notably, PD patients who have had dysphagia had a higher density of α-synuclein aggregates in the pharyngeal nerves than those without dysphagia. These findings indicate that motor involvement of the pharynx in PD is one of the factors leading to oropharyngeal dysphagia commonly seen in PD patients.

  9. α-Synuclein Pathology and Axonal Degeneration of the Peripheral Motor Nerves Innervating Pharyngeal Muscles in Parkinson’s Disease

    PubMed Central

    Mu, Liancai; Sobotka, Stanislaw; Chen, Jingming; Su, Hungxi; Sanders, Ira; Adler, Charles H.; Shill, Holly A.; Caviness, John N.; Samanta, Johan E.; Beach, Thomas G.

    2012-01-01

    Parkinson’s disease (PD) is a neurodegenerative disease primarily characterized by cardinal motor symptoms and central nervous system pathology. As current drug therapies can often stabilize these cardinal motor symptoms attention has shifted to the other motor and non-motor symptoms of PD which are resistant to drug therapy. Dysphagia in PD is perhaps the most important drug resistant symptom as it leads to aspiration and pneumonia, the leading cause of death. Here, we present direct evidence for degeneration of the pharyngeal motor nerves in PD. In this study, we examined the cervical vagal (X) nerve, pharyngeal branch of the X nerve (Ph-X), and pharyngeal plexus innervating the pharyngeal muscles in 14 postmortem specimens, 10 subjects with PD and 4 age-matched control subjects. Synucleinopathy in the pharyngeal nerves was detected using an immunohistochemical method for phosphorylated α-synuclein. α-Synuclein aggregates were revealed in the X nerve and Ph-X and immunoreactive intramuscular nerve twigs and axon terminals within the neuromuscular junctions were identified in all the PD subjects and in none of the controls. These findings indicate that the motor nervous system of the pharynx is involved in the pathological process of PD. Notably, PD subjects with dysphagia had a higher density of α-synuclein aggregates in the pharyngeal nerves as compared with those without dysphagia. Motor involvement of the pharynx in PD appears to be one of the factors leading to oropharyngeal dysphagia commonly seen in PD patients. PMID:23334595

  10. Activation of PI3K and R-Ras signaling promotes the extension of sensory axons on inhibitory chondroitin sulfate proteoglycans.

    PubMed

    Silver, Lee; Michael, James V; Goldfinger, Lawrence E; Gallo, Gianluca

    2014-09-01

    Chondroitin sulfate proteoglycans (CSPGs) are extracellular inhibitors of axon extension and plasticity, and cause growth cones to exhibit dystrophic behaviors. Phosphoinositide 3-kinase (PI3K) is a lipid kinase activated by axon growth promoting signals. In this study, we used embryonic chicken dorsal root ganglion neurons to determine if CSPGs impair signaling through PI3K. We report that CSPGs inhibit PI3K signaling in axons and growth cones, as evidenced by decreased levels of phosphorylated downstream kinases (Akt and S6). Direct activation of PI3K signaling, using a cell permeable phosphopeptide (PI3Kpep), countered the effects of CSPGs on growth cones and axon extension. Both overnight and acute treatment with PI3Kpep promoted axon extension on CSPG-coated substrates. The R-Ras GTPase is an upstream positive regulator of PI3K signaling. Expression of constitutively active R-Ras promoted axon extension and growth cone elaboration on CSPGs and permissive substrata. In contrast, an N-terminus-deleted constitutively active R-Ras, deficient in PI3K activation, promoted axon extension but not growth cone elaboration on CSPGs and permissive substrata. These data indicate that activation of R-Ras-PI3K signaling may be a viable approach for manipulating axon extension on CSPGs. © 2014 Wiley Periodicals, Inc.

  11. Peripheral neuropathy is a common manifestation of mitochondrial diseases: a single-centre experience.

    PubMed

    Luigetti, M; Sauchelli, D; Primiano, G; Cuccagna, C; Bernardo, D; Lo Monaco, M; Servidei, S

    2016-06-01

    Peripheral neuropathy in mitochondrial diseases (MDs) may vary from a subclinical finding in a multisystem syndrome to a severe, even isolated, manifestation in some patients. To investigate the involvement of the peripheral nervous system in MDs extensive electrophysiological studies were performed in 109 patients with morphological, biochemical and genetic diagnosis of MD [12 A3243G progressive external ophthalmoplegia (PEO)/mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), 16 myoclonic epilepsy with ragged-red fibres (MERRF), four mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), 67 PEO with single or multiple deletions of mitochondrial DNA, 10 others]. A neuropathy was found in 49 patients (45%). The incidence was very high in MNGIE (100%), MELAS (92%) and MERRF (69%), whilst 28% of PEO patients had evidence of peripheral involvement. The most frequent abnormality was a sensory axonal neuropathy found in 32/49 patients (65%). A sensory-motor axonal neuropathy was instead detected in 16% of the patients and sensory-motor axonal demyelinating neuropathy in 16%. Finally one Leigh patient had a motor axonal neuropathy. It is interesting to note that the great majority had preserved tendon reflexes and no sensory disturbances. In conclusion, peripheral involvement in MD is frequent even if often mild or asymptomatic. The correct identification and characterization of peripheral neuropathy through electrophysiological studies represents another tile in the challenge of MD diagnosis. © 2016 EAN.

  12. Novel cryoneurolysis device for the treatment of sensory and motor peripheral nerves.

    PubMed

    Ilfeld, Brian M; Preciado, Jessica; Trescot, Andrea M

    2016-08-01

    Cryoneurolysis is the direct application of low temperatures to reversibly ablate peripheral nerves to provide pain relief. Recent development of a handheld cryoneurolysis device with small gauge probes and an integrated skin warmer broadens the clinical applications to include treatment of superficial nerves, further enabling treatments for pre-operative pain, post-surgical pain, chronic pain, and muscle movement disorders. Cryoneurolysis is the direct application of cold temperatures to a peripheral nerve, resulting in reversible ablation due to Wallerian degeneration and nerve regeneration. Use over the last 50 years attests to a very low incidence of complications and adverse effects. Cryoprobes have traditionally been applied through a surgical incision; but, recent technical advances allow percutaneous administration. A new hand-held device is now approved for use within the United States. Cryoneurolysis has been used to treat postoperative and chronic pain states as well as spasticity. Expert commentary: Changes in the US healthcare system such as a push for the reduction of opioid use and the incorporation of Diagnostic Related Group codes, as well as recent technological advances including a handheld unit that allows for treatment of superficial nerves while protecting the skin from damage, may contribute to the resurgence of cryoneurolysis for the treatment of peripheral nerves.

  13. VEGF-B selectively regenerates injured peripheral neurons and restores sensory and trophic functions

    PubMed Central

    Guaiquil, Victor H.; Pan, Zan; Karagianni, Natalia; Fukuoka, Shima; Alegre, Gemstonn; Rosenblatt, Mark I.

    2014-01-01

    VEGF-B primarily provides neuroprotection and improves survival in CNS-derived neurons. However, its actions on the peripheral nervous system have been less characterized. We examined whether VEGF-B mediates peripheral nerve repair. We found that VEGF-B induced extensive neurite growth and branching in trigeminal ganglia neurons in a manner that required selective activation of transmembrane receptors and was distinct from VEGF-A–induced neuronal growth. VEGF-B–induced neurite elongation required PI3K and Notch signaling. In vivo, VEGF-B is required for normal nerve regeneration: mice lacking VEGF-B showed impaired nerve repair with concomitant impaired trophic function. VEGF-B treatment increased nerve regeneration, sensation recovery, and trophic functions of injured corneal peripheral nerves in VEGF-B–deficient and wild-type animals, without affecting uninjured nerves. These selective effects of VEGF-B on injured nerves and its lack of angiogenic activity makes VEGF-B a suitable therapeutic target to treat nerve injury. PMID:25404333

  14. Regeneration of diabetic axons is enhanced by selective knockdown of the PTEN gene

    PubMed Central

    Singh, Bhagat; Singh, Vandana; Krishnan, Anand; Koshy, Kurien; Martinez, Jose A.; Cheng, Chu; Almquist, Chris

    2014-01-01

    Diabetes mellitus renders both widespread and localized irreversible damage to peripheral axons while imposing critical limitations on their ability to regenerate. A major failure of regenerative capacity thereby imposes a ‘double hit’ in diabetic patients who frequently develop focal neuropathies such as carpal tunnel syndrome in addition to generalized diffuse polyneuropathy. The mechanisms of diabetic neuron regenerative failure have been speculative and few approaches have offered therapeutic opportunities. In this work we identify an unexpected but major role for PTEN upregulation in diabetic peripheral neurons in attenuating axon regrowth. In chronic diabetic neuropathy models in mice, we identified significant PTEN upregulation in peripheral sensory neurons of messenger RNA and protein compared to littermate controls. In vitro, sensory neurons from these mice responded to PTEN knockdown with substantial rises in neurite outgrowth and branching. To test regenerative plasticity in a chronic diabetic model with established neuropathy, we superimposed an additional focal sciatic nerve crush injury and assessed morphological, electrophysiological and behavioural recovery. Knockdown of PTEN in dorsal root ganglia ipsilateral to the side of injury was achieved using a unique form of non-viral short interfering RNA delivery to the ipsilateral nerve injury site and paw. In comparison with scrambled sequence control short interfering RNA, PTEN short interfering RNA improved several facets of regeneration: recovery of compound muscle action potentials, reflecting numbers of reconnected motor axons to endplates, conduction velocities of both motor and sensory axons, reflecting their maturation during regrowth, numbers and calibre of regenerating myelinated axons distal to the injury site, reinnervation of the skin by unmyelinated epidermal axons and recovery of mechanical sensation. Collectively, these findings identify a novel therapeutic approach, potentially

  15. Peripheral tactile sensory perception of older adults improved using subsensory electrical noise stimulation.

    PubMed

    Breen, Paul P; Serrador, Jorge M; O'Tuathail, Claire; Quinlan, Leo R; McIntosh, Caroline; ÓLaighin, Gearóid

    2016-08-01

    Loss of tactile sensory function is common with aging and can lead to numbness and difficulty with balance and gait. In previous work we found that subsensory electrical noise stimulation (SENS) applied to the tibial nerve improved tactile perception in the soles of the feet of healthy adults. In this work we aimed to determine if SENS remained effective in an older adult population with significant levels of sensory loss. Older adult subjects (N=8, female = 4, aged 65-80) had SENS applied via surface electrodes placed proximally to the medial and lateral malleoli. Vibration perception thresholds (VPTs) were assessed in six conditions, two control conditions (no SENS) and four SENS conditions (zero mean ±15µA, 30µA, 45µA and 60µA SD). VPT was assessed at three sites on the plantar aspect of the foot. Vibration perception was significantly improved in the presence of ±30µA SENS and by 16.2±2.4% (mean ± s.e.m.) when optimised for each subject. The improvement in perception was similar across all VPT test sites. Copyright © 2016 IPEM. All rights reserved.

  16. Impaired basal thermal homeostasis in rats lacking capsaicin-sensitive peripheral small sensory neurons.

    PubMed

    Yamashita, Hitoshi; Wang, Zuocheng; Wang, Youxue; Furuyama, Tatsuo; Kontani, Yasuhide; Sato, Yuzo; Mori, Nozomu

    2008-03-01

    We studied the effects of selective loss of capsaicin-sensitive primary sensory neurons on thermosensation and thermoregulation in rats. Neonatal capsaicin treatment in rats caused a remarkable decrease in the number of small-diameter neurons in the dorsal root ganglion (DRG) compared with their number in the control rats. Gene expression analysis for various thermo-sensitive transient receptor potential (TRP) channels indicated marked reductions in the mRNA levels of TRPV1 (70%), TRPM8 (46%) and TRPA1 (64%), but not of TRPV2, in the DRG of capsaicin-treated rats compared with those in the control rats. In addition to the heat and cold insensitivity, capsaicin-treated rats showed lower rectal core temperature, higher skin temperature and decreased sensitivity to ambient temperature alteration under normal housing at room temperature, suggesting impaired thermosensation and change in thermoregulation in the rats. Uncoupling protein 1 (UCP1) expression and the thermogenic ability in brown adipose tissues were attenuated in the capsaicin-treated rats. These results indicate a critical role of capsaicin-sensitive sensory neurons in both heat and cool sensation and hence in basal thermal homeostasis, which is balanced by heat release and production including UCP1 thermogenesis, following sensation of the ambient temperature.

  17. The sensory trigeminal system in birds: input, organization and effects of peripheral damage. A review.

    PubMed

    Dubbeldam, J L

    1998-12-01

    The primary sensory trigeminal system in birds comprises the mesencephalic trigeminal nucleus and the trigeminal ganglion with projections to the principal sensory nucleus (PrV) and the descending tract with its subnuclei. Other cranial nerves can contribute to PrV and the descending system that together form the somatosensory system of the head. There is also a proprioceptive component. The somatosensory system comprises a component serving tactile sense and a nociceptive component. The former processes information from many mechanoreceptors in beak and tongue; both PrV and subnuclei of the descending system are involved. The nociceptive component consists of small ganglion cells projecting presumably to layers I and II of the caudal subnucleus of the descending trigeminal system and cervical dorsal horn; this is the only trigeminal region showing immunoreactivity for substance P. The effects of amputation of the tips of the beak of chickens (debeaking) are estimated by fiber counts in electron microscopic preparations of the trigeminal branches innervating that area, and by cell counts in Nissl stained sections of the trigeminal ganglion. Our data indicate that debeaking causes a loss of exteroceptive units, but not of nociceptive units. Comparison of sections stained for the presence of substance P (immunohistochemistry) did not reveal a long-term effect on the nociceptive system suggestive of the occurrence of chronic pain.

  18. Autosomal dominant sensory ataxia: a neuroaxonal dystrophy.

    PubMed

    Moeller, Jeremy J; Macaulay, Robert J B; Valdmanis, Paul N; Weston, Lyle E; Rouleau, Guy A; Dupré, Nicolas

    2008-09-01

    Autosomal dominant sensory ataxia (ADSA), a rare hereditary ataxia, is characterized by progressive dysfunction of central sensory pathways. Its pathological features have not been previously documented. We report a case of a 61-year-old man with ADSA who died of congestive heart failure. Autopsy specimens of brain, thoracolumbar spinal cord, peripheral nerve and skeletal muscle were examined. There was no abnormality on gross examination. Microscopically, there were occasional swollen axons within the cerebral cortex and deep nuclei, particularly the subthalamic nucleus, with no neuronal loss, gliosis or microglial activation. There were many axonal spheroids within the medulla, particularly in the dorsal column nuclei. Axonal spheroids were also seen in the dorsal columns and ventral horns in the thoracolumbar spinal cord, but there was no Wallerian degeneration or demyelination. Amyloid precursor protein (APP) immunostaining of some of the spheroids suggested continuing dysfunction of axoplasmic flow in some regions. There was mild inflammation of peripheral nerve roots but no spheroid, and patchy chronic inflammation of skeletal muscle. In summary, the major pathological process in ADSA is a neuroaxonal dystrophy most prominent in the dorsal columns and dorsal column nuclei, consistent with the clinical pattern of central sensory pathway degeneration.

  19. Sexual dimorphism of the electrosensory system: a quantitative analysis of nerve axons in the dorsal anterior lateral line nerve of the blue-spotted Fantail Stingray (Taeniura lymma).

    PubMed

    Kempster, R M; Garza-Gisholt, E; Egeberg, C A; Hart, N S; O'Shea, O R; Collin, S P

    2013-01-01

    Quantitative studies of sensory axons provide invaluable insights into the functional significance and relative importance of a particular sensory modality. Despite the important role electroreception plays in the behaviour of elasmobranchs, to date, there have been no studies that have assessed the number of electrosensory axons that project from the peripheral ampullae to the central nervous system (CNS). The complex arrangement and morphology of the peripheral electrosensory system has a significant influence on its function. However, it is not sufficient to base conclusions about function on the peripheral system alone. To fully appreciate the function of the electrosensory system, it is essential to also assess the neural network that connects the peripheral system to the CNS. Using stereological techniques, unbiased estimates of the total number of axons were obtained for both the electrosensory bundles exiting individual ampullary organs and those entering the CNS (via the dorsal root of the anterior lateral line nerve, ALLN) in males and females of different sizes. The dorsal root of the ALLN consists solely of myelinated electrosensory axons and shows both ontogenetic and sexual dimorphism. In particular, females exhibit a greater abundance of electrosensory axons, which may result in improved sensitivity of the electrosensory system and may facilitate mate identification for reproduction. Also presented are detailed morphological data on the peripheral electrosensory system to allow a complete interpretation of the functional significance of the sexual dimorphism found in the ALLN. © 2013 S. Karger AG, Basel.

  20. FAK Is Required for Schwann Cell Spreading on Immature Basal Lamina to Coordinate the Radial Sorting of Peripheral Axons with Myelination

    PubMed Central

    Grove, Matthew

    2014-01-01

    Without Focal Adhesion Kinase (FAK), developing murine Schwann cells (SCs) proliferate poorly, sort axons inefficiently, and cannot myelinate peripheral nerves. Here we show that FAK is required for the development of SCs when their basal lamina (BL) is fragmentary, but not when it is mature in vivo. Mutant SCs fail to spread on fragmentary BL during development in vivo, and this is phenocopied by SCs lacking functional FAK on low laminin (LN) in vitro. Furthermore, SCs without functional FAK initiate differentiation prematurely, both in vivo and in vitro. In contrast to their behavior on high levels of LN, SCs lacking functional FAK grown on low LN display reduced spreading, proliferation, and indicators of contractility (i.e., stress fibers, arcs, and focal adhesions) and are primed to differentiate. Growth of SCs lacking functional FAK on increasing LN concentrations in vitro revealed that differentiation is not regulated by G1 arrest but rather by cell spreading and the level of contractile actomyosin. The importance of FAK as a critical regulator of the specific response of developing SCs to fragmentary BL was supported by the ability of adult FAK mutant SCs to remyelinate demyelinated adult nerves on mature BL in vivo. We conclude that FAK promotes the spreading and actomyosin contractility of immature SCs on fragmentary BL, thus maintaining their proliferation, and preventing differentiation until they reach high density, thereby promoting radial sorting. Hence, FAK has a critical role in the response of SCs to limiting BL by promoting proliferation and preventing premature SC differentiation. PMID:25274820

  1. Calcium-activated potassium channel SK1 is widely expressed in the peripheral nervous system and sensory organs of adult zebrafish.

    PubMed

    Cabo, R; Zichichi, R; Viña, E; Guerrera, M C; Vázquez, G; García-Suárez, O; Vega, J A; Germanà, A

    2013-10-25

    Sensory cells contain ion channels involved in the organ-specific transduction mechanisms that convert different types of stimuli into electric energy. Here we focus on small-conductance calcium-activated potassium channel 1 (SK1) which plays an important role in all excitable cells acting as feedback regulators in after-hyperpolarization. This study was undertaken to analyze the pattern of expression of SK1 in the zebrafish peripheral nervous system and sensory organs using RT-PRC, Westernblot and immunohistochemistry. Expression of SK1 mRNA was observed at all developmental stages analyzed (from 10 to 100 days post fertilization, dpf), and the antibody used identified a protein with a molecular weight of 70kDa, at 100dpf (regarded to be adult). Cell expressing SK1 in adult animals were neurons of dorsal root and cranial nerve sensory ganglia, sympathetic neurons, sensory cells in neuromasts of the lateral line system and taste buds, crypt olfactory neurons and photoreceptors. Present results report for the first time the expression and the distribution of SK1 in the peripheral nervous system and sensory organs of adult zebrafish, and may contribute to set zebrafish as an interesting experimental model for calcium-activated potassium channels research. Moreover these findings are of potential interest because the potential role of SK as targets for the treatment of neurological diseases and sensory disorders.

  2. IB4-binding sensory neurons in the adult rat express a novel 3′ UTR-extended isoform of CaMK4 that is associated with its localization to axons

    PubMed Central

    Harrison, Benjamin J.; Flight, Robert M.; Gomes, Cynthia; Venkat, Gayathri; Ellis, Steven R; Sankar, Uma; Twiss, Jeffery L.; Rouchka, Eric C.; Petruska, Jeffrey C.

    2013-01-01

    Calcium/Calmodulin-dependent protein Kinase 4 (Gene and transcript: CaMK4; Protein: CaMKIV) is the nuclear effector of the Ca2+/Calmodulin Kinase (CaMK) pathway where it co-ordinates transcriptional responses. However, CaMKIV is present in the cytoplasm and axons of subpopulations of neurons, including some sensory neurons of the dorsal root ganglia (DRG), suggesting an extra-nuclear role for this protein. We observed that CaMKIV was expressed strongly in the cytoplasm and axons of a subpopulation of small diameter DRG neurons, most likely cutaneous nociceptors by virtue of their binding the isolectin IB4. In IB4+ spinal nerve axons, 20% of CaMKIV was co-localized with the endocytic marker Rab7 in axons that highly expressed CAM-Kinase-Kinase (CAMKK), an upstream activator of CaMKIV, suggesting a role for CaMKIV in signalling though signalling endosomes. Using fluorescent in situ hybridization (FISH) with riboprobes, we also observed that small diameter neurons expressed high levels of a novel 3' untranslated region (UTR) variant of CaMK4 mRNA. Using rapid amplification of cDNA ends (RACE), RT-PCR with gene-specific primers, and cDNA sequencing analyses we determined that the novel transcript contains an additional 10kb beyond the annotated gene terminus to a highly conserved alternate poly-adenylation site. qPCR analyses of fluorescent-activated cell sorted (FACS) DRG neurons confirmed that this 3'UTR-extended variant was preferentially expressed in IB4-binding neurons. Computational analyses of the 3'-UTR sequence predict that UTR-extension introduces consensus sites for RNA-binding proteins (RBPs) including the Embryonic Lethal Abnormal Vision (ELAV)/Hu family proteins. We consider the possible implications of axonal CaMKIV in the context of the unique properties of IB4-binding DRG neurons. PMID:23817991

  3. Phenotypic switching of nonpeptidergic cutaneous sensory neurons following peripheral nerve injury.

    PubMed

    Wang, Ting; Molliver, Derek C; Jing, Xiaotang; Schwartz, Erica S; Yang, Fu-Chia; Samad, Omar Abdel; Ma, Qiufu; Davis, Brian M

    2011-01-01

    In adult mammals, the phenotype of half of all pain-sensing (nociceptive) sensory neurons is tonically modulated by growth factors in the glial cell line-derived neurotrophic factor (GDNF) family that includes GDNF, artemin (ARTN) and neurturin (NRTN). Each family member binds a distinct GFRα family co-receptor, such that GDNF, NRTN and ARTN bind GFRα1, -α2, and -α3, respectively. Previous studies revealed transcriptional regulation of all three receptors in following axotomy, possibly in response to changes in growth factor availability. Here, we examined changes in the expression of GFRα1-3 in response to injury in vivo and in vitro. We found that after dissociation of adult sensory ganglia, up to 27% of neurons die within 4 days (d) in culture and this can be prevented by nerve growth factor (NGF), GDNF and ARTN, but not NRTN. Moreover, up-regulation of ATF3 (a marker of neuronal injury) in vitro could be prevented by NGF and ARTN, but not by GDNF or NRTN. The lack of NRTN efficacy was correlated with rapid and near-complete loss of GFRα2 immunoreactivity. By retrogradely-labeling cutaneous afferents in vivo prior to nerve cut, we demonstrated that GFRα2-positive neurons switch phenotype following injury and begin to express GFRα3 as well as the capsaicin receptor, transient receptor potential vanilloid 1(TRPV1), an important transducer of noxious stimuli. This switch was correlated with down-regulation of Runt-related transcription factor 1 (Runx1), a transcription factor that controls expression of GFRα2 and TRPV1 during development. These studies show that NRTN-responsive neurons are unique with respect to their plasticity and response to injury, and suggest that Runx1 plays an ongoing modulatory role in the adult.

  4. Peripheral fatigue limits endurance exercise via a sensory feedback-mediated reduction in spinal motoneuronal output

    PubMed Central

    Venturelli, Massimo; Ives, Stephen J.; McDaniel, John; Layec, Gwenael; Rossman, Matthew J.; Richardson, Russell S.

    2013-01-01

    This study sought to determine whether afferent feedback associated with peripheral muscle fatigue inhibits central motor drive (CMD) and thereby limits endurance exercise performance. On two separate days, eight men performed constant-load, single-leg knee extensor exercise to exhaustion (85% of peak power) with each leg (Leg1 and Leg2). On another day, the performance test was repeated with one leg (Leg1) and consecutively (within 10 s) with the other/contralateral leg (Leg2-post). Exercise-induced quadriceps fatigue was assessed by reductions in potentiated quadriceps twitch-force from pre- to postexercise (ΔQtw,pot) in response to supramaximal magnetic femoral nerve stimulation. The output from spinal motoneurons, estimated from quadriceps electromyography (iEMG), was used to reflect changes in CMD. Rating of perceived exertion (RPE) was recorded during exercise. Time to exhaustion (∼9.3 min) and exercise-induced ΔQtw,pot (∼51%) were similar in Leg1 and Leg2 (P > 0.5). In the consecutive leg trial, endurance performance of the first leg was similar to that observed during the initial trial (∼9.3 min; P = 0.8); however, time to exhaustion of the consecutively exercising contralateral leg (Leg2-post) was shorter than the initial Leg2 trial (4.7 ± 0.6 vs. 9.2 ± 0.4 min; P < 0.01). Additionally, ΔQtw,pot following Leg2-post was less than Leg2 (33 ± 3 vs 52 ± 3%; P < 0.01). Although the slope of iEMG was similar during Leg2 and Leg2-post, end-exercise iEMG following Leg2-post was 26% lower compared with Leg2 (P < 0.05). Despite a similar rate of rise, RPE was consistently ∼28% higher throughout Leg2-post vs. Leg2 (P < 0.05). In conclusion, this study provides evidence that peripheral fatigue and associated afferent feedback limits the development of peripheral fatigue and compromises endurance exercise performance by inhibiting CMD. PMID:23722705

  5. Depending on Its Nano-Spacing, ALCAM Promotes Cell Attachment and Axon Growth

    PubMed Central

    Thelen, Karsten; Jaehrling, Steffen; Spatz, Joachim P.; Pollerberg, G. Elisabeth

    2012-01-01

    ALCAM is a member of the cell adhesion molecule (CAM) family which plays an important role during nervous system formation. We here show that the two neuron populations of developing dorsal root ganglia (DRG) display ALCAM transiently on centrally and peripherally projecting axons during the two phases of axon outgrowth. To analyze the impact of ALCAM on cell adhesion and axon growth, DRG single cells were cultured on ALCAM-coated coverslips or on nanopatterns where ALCAM is presented in physiological amino-carboxyl terminal orientation at highly defined distances (29, 54, 70, 86, and 137 nm) and where the interspaces are passivated to prevent unspecific protein deposition. Some axonal features (branching, lateral deviation) showed density dependence whereas others (number of axons per neuron, various axon growth parameters) turned out to be an all-or-nothing reaction. Time-lapse analyses revealed that ALCAM density has an impact on axon velocity and advance efficiency. The behavior of the sensory axon tip, the growth cone, partially depended on ALCAM density in a dose-response fashion (shape, dynamics, detachment) while other features did not (size, complexity). Whereas axon growth was equally promoted whether ALCAM was presented at high (29 nm) or low densities (86 nm), the attachment of non-neuronal cells depended on high ALCAM densities. The attachment of non-neuronal cells to the rather unspecific standard proteins presented by conventional implants designed to enhance axonal regeneration is a severe problem. Our findings point to ALCAM, presented as 86 nm pattern, for a promising candidate for the improvement of such implants since this pattern drives axon growth to its full extent while at the same time non-neuronal cell attachment is clearly reduced. PMID:23251325

  6. Axonal Localization of Integrins in the CNS Is Neuronal Type and Age Dependent

    PubMed Central

    Soleman, Sara; Mason, Matthew R. J.; Verhaagen, Joost; Bensadoun, Jean-Charles; Aebischer, Patrick

    2016-01-01

    The regenerative ability of CNS axons decreases with age, however, this ability remains largely intact in PNS axons throughout adulthood. These differences are likely to correspond with age-related silencing of proteins necessary for axon growth and elongation. In previous studies, it has been shown that reintroduction of the α9 integrin subunit (tenascin-C receptor, α9) that is downregulated in adult CNS can improve neurite outgrowth and sensory axon regeneration after a dorsal rhizotomy or a dorsal column crush spinal cord lesion. In the current study, we demonstrate that virally expressed integrins (α9, α6, or β1 integrin) in the adult rat sensorimotor cortex and adult red nucleus are excluded from axons following neuronal transduction. Attempts to stimulate transport by inclusion of a cervical spinal injury and thus an upregulation of extracellular matrix molecules at the lesion site, or cotransduction with its binding partner, β1 integrin, did not induce integrin localization within axons. In contrast, virally expressed α9 integrin in developing rat cortex (postnatal day 5 or 10) demonstrated clear localization of integrins in cortical axons revealed by the presence of integrin in the axons of the corpus callosum and internal capsule, as well as in the neuronal cell body. Furthermore, examination of dorsal root ganglia neurons and retinal ganglion cells demonstrated integrin localization both within peripheral nerve as well as dorsal root axons and within optic nerve axons, respectively. Together, our results suggest a differential ability for in vivo axonal transport of transmembrane proteins dependent on neuronal age and subtype. PMID:27570822

  7. Efferent axons in the avian auditory nerve.

    PubMed

    Köppl, C

    2001-05-01

    The sensory hair cells of the inner ear receive both afferent and efferent innervation. The efferent supply to the auditory organ has evolved in birds and mammals into a separate complex system, with several types of neurons of largely unknown function. In this study, the efferent axons in four different species of birds (chicken, starling, barn owl and emu) were examined anatomically. Total numbers of efferents supplying the cochlear duct (auditory basilar papilla and the vestibular lagenar macula) were determined; separate estimates of the efferents to the lagenar macula only were also derived and subtracted. The numbers for auditory efferents thus varied between 120 (chicken) and 1068 (barn owl). Considering the much larger numbers of hair cells in the basilar papilla, each efferent is predicted to branch extensively. However, pronounced species-specific differences as well as regional differences along the tonotopic gradient of the basilar papilla were documented. Myelinated and unmyelinated axons were found, with mean diameters of about 1 microm and about 0.5 microm, respectively. This suggests two basic populations of efferents, however, they did not appear to be distinguished sharply. Evidence is presented that some efferents lose their myelination at the transition from central oligodendrocyte to peripheral Schwann cell myelin. Finally, a comparison of the four bird species evaluated suggests that the efferent population with smaller, unmyelinated axons is the phylogenetically more primitive one. A new population probably arose in parallel with the evolution and differentiation of the specialized hair-cell type it innervates, the short hair cell.

  8. Mechanisms of diabetic neuropathy: axon dysfunction.

    PubMed

    Sima, Anders A F; Zhang, Weixian

    2014-01-01

    Diabetic neuropathy is the most common complication of diabetes. It shows a progressive development with sensory loss, pain and autonomic dysfunction as common symptoms. Pathologically it is characterized by a series of interrelated metabolic abnormalities with insulin deficiency and hyperglycemia as the initiating culprits. The neuropathy accompanying type 2DM (insulin resistance) and type 1DM (insulin deficiency) appears to differ as to their structural changes; the former showing a milder axonal involvement and segmental myelin breakdown, whereas the latter shows a more severe axonal atrophy and axonal loss. Based mainly on animal data we will describe the sequential neuropathologic changes and differences in the two types of diabetes. These differences are related to differences in a myriad of underlying sequential metabolic abnormalities, which will be dealt with in detail. How metabolic defects affect nerve function will be elaborated upon. The disorder does not only involve somatic peripheral nerves but also autonomic and central nerve tracts. Today no successful therapy exists for diabetic neuropathy. During the last 30 years several experimental drugs targeting the polyol-pathway and oxidative stress have been tested, but with limited or no success. Instead therapies targeting the initiating and overriding pathogenetic abnormalities, such as insulin-deficiency and hyperglycemia need to be employed. One such agent is the insulinomimetic C-peptide which has demonstrated significant therapeutic and preventive effects in type 1 diabetic patients. Not surprisingly this has been particularly successful following early intervention. However diabetic neuropathy still remains a major medical problem affecting millions of patients.

  9. TRPA1 receptor localisation in the human peripheral nervous system and functional studies in cultured human and rat sensory neurons.

    PubMed

    Anand, U; Otto, W R; Facer, P; Zebda, N; Selmer, I; Gunthorpe, M J; Chessell, I P; Sinisi, M; Birch, R; Anand, P

    2008-06-20

    TRPA1 is a receptor expressed by sensory neurons, that is activated by low temperature (<17 degrees C) and plant derivatives such as cinnamaldehyde and isoeugenol, to elicit sensations including pain. Using immunohistochemistry, we have, for the first time, localised TRPA1 in human DRG neurons, spinal cord motoneurones and nerve roots, peripheral nerves, intestinal myenteric plexus neurones, and skin basal keratinocytes. TRPA1 co-localised with a subset of hDRG neurons positive for TRPV1, the heat and capsaicin receptor. The number of small/medium TRPA1 positive neurons (< or =50 microm) was increased after hDRG avulsion injury [percentage of cells, median (range): controls 16.5 (7-23); injured 46 (34-55); P<0.005], but the number of large TRPA1 neurons was unchanged [control 19.5 (13-31); injured 21 (11-35)]. Similar TRPA1 changes were observed in cultured hDRG neurons, after exposure to a combination of key neurotrophic factors NGF, GDNF and NT-3 (NTFs) in vitro. We used calcium imaging to examine responses of HEK cells transfected with hTRPA1 cDNA, and of human and rat DRG neurons cultured with or without added NTFs, to cinnamaldehyde (CA) and isoeugenol (IE). Exposure to NTFs in vitro sensitized cultured human sensory neuronal responses to CA; repeated CA exposure produced desensitisation. In rDRG neurons, low (225 microM) CA preincubation enhanced capsaicin responses, while high (450 microM and 2mM) CA caused inhibition which was partially reversed in the presence of 8 bromo cAMP, indicating receptor dephosphorylation. While TRPA1 localisation is more widespread than TRPV1, it represents a promising novel drug target for the treatment of chronic pain and hypersensitivity.

  10. Microglial responses around intrinsic CNS neurons are correlated with axonal regeneration

    PubMed Central

    2010-01-01

    Background Microglia/macrophages and lymphocytes (T-cells) accumulate around motor and primary sensory neurons that are regenerating axons but there is little or no microglial activation or T-cell accumulation around axotomised intrinsic CNS neurons, which do not normally regenerate axons. We aimed to establish whether there was an inflammatory response around the perikarya of CNS neurons that were induced to regenerate axons through a peripheral nerve graft. Results When neurons of the thalamic reticular nucleus (TRN) and red nucleus were induced to regenerate axons along peripheral nerve grafts, a marked microglial response was found around their cell bodies, including the partial enwrapping of some regenerating neurons. T-cells were found amongst regenerating TRN neurons but not rubrospinal neurons. Axotomy alone or insertion of freeze-killed nerve grafts did not induce a similar perineuronal inflammation. Nerve grafts in the corticospinal tracts did not induce axonal regeneration or a microglial or T-cell response in the motor cortex. Conclusions These results strengthen the evidence that perineuronal microglial accumulation (but not T-cell accumulation) is involved in axonal regeneration by intrinsic CNS and other neurons. PMID:20137064

  11. Microglial responses around intrinsic CNS neurons are correlated with axonal regeneration.

    PubMed

    Shokouhi, Bahman N; Wong, Bernadette Z Y; Siddiqui, Samir; Lieberman, A Robert; Campbell, Gregor; Tohyama, Koujiro; Anderson, Patrick N

    2010-02-05

    Microglia/macrophages and lymphocytes (T-cells) accumulate around motor and primary sensory neurons that are regenerating axons but there is little or no microglial activation or T-cell accumulation around axotomised intrinsic CNS neurons, which do not normally regenerate axons. We aimed to establish whether there was an inflammatory response around the perikarya of CNS neurons that were induced to regenerate axons through a peripheral nerve graft. When neurons of the thalamic reticular nucleus (TRN) and red nucleus were induced to regenerate axons along peripheral nerve grafts, a marked microglial response was found around their cell bodies, including the partial enwrapping of some regenerating neurons. T-cells were found amongst regenerating TRN neurons but not rubrospinal neurons. Axotomy alone or insertion of freeze-killed nerve grafts did not induce a similar perineuronal inflammation. Nerve grafts in the corticospinal tracts did not induce axonal regeneration or a microglial or T-cell response in the motor cortex. These results strengthen the evidence that perineuronal microglial accumulation (but not T-cell accumulation) is involved in axonal regeneration by intrinsic CNS and other neurons.

  12. Microfluidic control of axonal guidance

    NASA Astrophysics Data System (ADS)

    Gu, Ling; Black, Bryan; Ordonez, Simon; Mondal, Argha; Jain, Ankur; Mohanty, Samarendra

    2014-10-01

    The precision of axonal pathfinding and the accurate formation of functional neural circuitry are crucial for an organism during development as well as during adult central and peripheral nerve regeneration. While chemical cues are believed to be primarily responsible for axonal pathfinding, we hypothesize that forces due to localized fluid flow may directly affect neuronal guidance during early organ development. Here, we report direct evidence of fluid flow influencing axonal migration, producing turning angles of up to 90°. Microfluidic flow simulations indicate that an axon may experience significant bending force due to cross-flow, which may contribute to the observed axonal turning. This method of flow-based guidance was successfully used to fasciculate one advancing axon onto another, showcasing the potential of this technique to be used for the formation of in vitro neuronal circuits.

  13. Unique Function of Kinesin Kif5A in Localization of Mitochondria in Axons

    PubMed Central

    Campbell, Philip D.; Shen, Kimberle; Sapio, Matthew R.; Glenn, Thomas D.; Talbot, William S.

    2014-01-01

    Mutations in Kinesin proteins (Kifs) are linked to various neurological diseases, but the specific and redundant functions of the vertebrate Kifs are incompletely understood. For example, Kif5A, but not other Kinesin-1 heavy-chain family members, is implicated in Charcot-Marie-Tooth disease (CMT) and Hereditary Spastic Paraplegia (HSP), but the mechanism of its involvement in the progressive axonal degeneration characteristic of these diseases is not well understood. We report that zebrafish kif5Aa mutants exhibit hyperexcitability, peripheral polyneuropathy, and axonal degeneration reminiscent of CMT and HSP. Strikingly, although kif5 genes are thought to act largely redundantly in other contexts, and zebrafish peripheral neurons express five kif5 genes, kif5Aa mutant peripheral sensory axons lack mitochondria and degenerate. We show that this Kif5Aa-specific function is cell autonomous and is mediated by its C-terminal tail, as only Kif5Aa and chimeric motors containing the Kif5Aa C-tail can rescue deficits. Finally, concurrent loss of the kinesin-3, kif1b, or its adaptor kbp, exacerbates axonal degeneration via a nonmitochondrial cargo common to Kif5Aa. Our results shed light on Kinesin complexity and reveal determinants of specific Kif5A functions in mitochondrial transport, adaptor binding, and axonal maintenance. PMID:25355224

  14. Inherited peripheral neuropathies.

    PubMed

    Shy, Michael E

    2011-04-01

    Mutations in genes expressed in Schwann cells and the axons they ensheathe cause the hereditary motor and sensory neuropathies, also known as Charcot-Marie-Tooth disease (CMT). More than 40 different genes have been shown to cause inherited neuropathies; chromosomal localizations of many other distinct inherited neuropathies have been mapped, and new genetic causes for inherited neuropathies continue to be discovered. How to keep track of all of these disorders, when to pursue genetic testing, and what tests to order for specific patients are difficult challenges for any neurologist. This review addresses these issues and provides illustrative cases to help in dealing with them. CMT serves as a living system to identify molecules necessary for normal peripheral nervous system (PNS) function. Understanding how these various molecules interact will provide a better understanding of the pathogenesis of peripheral neuropathies in general as well as other neurodegenerative disorders involving the PNS.

  15. Inflammation of peripheral tissues and injury to peripheral nerves induce differing effects in the expression of the calcium-sensitive N-arachydonoylethanolamine-synthesizing enzyme and related molecules in rat primary sensory neurons.

    PubMed

    Sousa-Valente, João; Varga, Angelika; Torres-Perez, Jose Vicente; Jenes, Agnes; Wahba, John; Mackie, Ken; Cravatt, Benjamin; Ueda, Natsuo; Tsuboi, Kazuhito; Santha, Peter; Jancso, Gabor; Tailor, Hiren; Avelino, António; Nagy, Istvan

    2017-06-01

    Elevation of intracellular Ca(2+) concentration induces the synthesis of N-arachydonoylethanolamine (anandamide) in a subpopulation of primary sensory neurons. N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD) is the only known enzyme that synthesizes anandamide in a Ca(2+) -dependent manner. NAPE-PLD mRNA as well as anandamide's main targets, the excitatory transient receptor potential vanilloid type 1 ion channel (TRPV1), the inhibitory cannabinoid type 1 (CB1) receptor, and the main anandamide-hydrolyzing enzyme fatty acid amide hydrolase (FAAH), are all expressed by subpopulations of nociceptive primary sensory neurons. Thus, NAPE-PLD, TRPV1, the CB1 receptor, and FAAH could form an autocrine signaling system that could shape the activity of a major subpopulation of nociceptive primary sensory neurons, contributing to the development of pain. Although the expression patterns of TRPV1, the CB1 receptor, and FAAH have been comprehensively elucidated, little is known about NAPE-PLD expression in primary sensory neurons under physiological and pathological conditions. This study shows that NAPE-PLD is expressed by about one-third of primary sensory neurons, the overwhelming majority of which also express nociceptive markers as well as the CB1 receptor, TRPV1, and FAAH. Inflammation of peripheral tissues and injury to peripheral nerves induce differing but concerted changes in the expression pattern of NAPE-PLD, the CB1 receptor, TRPV1, and FAAH. Together these data indicate the existence of the anatomical basis for an autocrine signaling system in a major proportion of nociceptive primary sensory neurons and that alterations in that autocrine signaling by peripheral pathologies could contribute to the development of both inflammatory and neuropathic pain.

  16. Disruption and restoration of dorsal horn sensory map after peripheral nerve crush and regeneration.

    PubMed

    Sugimoto, T; Yoshida, A; Nishijima, K; Ichikawa, H

    1995-10-01

    Formalin injection into the hindpaw of rats produces many neurons with c-fos protein-like immunoreactivity (fos-neurons) in the medial 3/4 of the ipsilateral dorsal horn laminae I and II at the junction of 4th and 5th lumbar segments (the sciatic territory). The tibial nerve transection 2 or 3 days earlier resulted in almost complete elimination of stimulation-induced fos-neurons in the tibial territory (medial 1/2 of the sciatic territory). When the animals had been conditioned by crushing the tibial nerve 2 weeks before stimulation (11 or 12 days before transection), the number of fos-neurons significantly increased compared to simple transection alone. The increase (2.5-fold) was greatest in the tibial territory. Therefore, the dorsal horn neurons in the deafferented tibial territory exhibited hypersensitivity to intact peroneal primary input, and the somatotopy map was disrupted. When the nerve had been crushed 3 weeks (18 or 19 days earlier than transection) rather than 2 weeks before stimulation, however, the number and distribution of fos-neurons were not different from those without conditioning (transection alone). Regenerated tibial nerve fibers were capable of transganglionic transport of WGA-HRP from the hindpaw receptive field to the tibial territory of the dorsal horn by 3 weeks but not by 2 weeks following the nerve crush. When transection was omitted, noxious signal transmitted through the tibial nerve fibers regenerated by 3 weeks after crush was capable of inducing c-fos in the tibial territory. The injury-induced hypersensitivity of dorsal horn neurons and resulting disruption of somatotopy map were reversed by re-establishment of peripheral tissue-nerve interaction.

  17. Protein synthetic machinery and mRNA in regenerating tips of spinal cord axons in lamprey.

    PubMed

    Jin, Li-Qing; Pennise, Cynthia R; Rodemer, William; Jahn, Kristen S; Selzer, Michael E

    2016-12-01

    Polyribosomes, mRNA, and other elements of translational machinery have been reported in peripheral nerves and in elongating injured axons of sensory neurons in vitro, primarily in growth cones. Evidence for involvement of local protein synthesis in regenerating central nervous system (CNS) axons is less extensive. We monitored regeneration of back-labeled lamprey spinal axons after spinal cord transection and detected mRNA in axon tips by in situ hybridization and microaspiration of their axoplasm. Poly(A)+mRNA was present in the axon tips, and was more abundant in actively regenerating tips than in static or retracting ones. Target-specific polymerase chain reaction (PCR) and in situ hybridization revealed plentiful mRNA for the low molecular neurofilament subunit and β-tubulin, but very little for β-actin, consistent with the morphology of their tips, which lack filopodia and lamellipodia. Electron microscopy showed ribosomes/polyribosomes in the distal parts of axon tips and in association with vesicle-like membranes, primarily in the tip. In one instance, there were structures with the appearance of rough endoplasmic reticulum. Immunohistochemistry showed patches of ribosomal protein S6 positivity in a similar distribution. The results suggest that local protein synthesis might be involved in the mechanism of axon regeneration in the lamprey spinal cord. J. Comp. Neurol. 524:3614-3640, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  18. Long-term characterization of axon regeneration and matrix changes using multiple channel bridges for spinal cord regeneration.

    PubMed

    Tuinstra, Hannah M; Margul, Daniel J; Goodman, Ashley G; Boehler, Ryan M; Holland, Samantha J; Zelivyanskaya, Marina L; Cummings, Brian J; Anderson, Aileen J; Shea, Lonnie D

    2014-03-01

    Spinal cord injury (SCI) results in loss of sensory and motor function below the level of injury and has limited available therapies. The host response to SCI is typified by limited endogenous repair, and biomaterial bridges offer the potential to alter the microenvironment to promote regeneration. Porous multiple channel bridges implanted into the injury provide stability to limit secondary damage and support cell infiltration that limits cavity formation. At the same time, the channels provide a path that physically directs axon growth across the injury. Using a rat spinal cord hemisection injury model, we investigated the dynamics of axon growth, myelination, and scar formation within and around the bridge in vivo for 6 months, at which time the bridge has fully degraded. Axons grew into and through the channels, and the density increased overtime, resulting in the greatest axon density at 6 months postimplantation, despite complete degradation of the bridge by that time point. Furthermore, the persistence of these axons contrasts with reports of axonal dieback in other models and is consistent with axon stability resulting from some degree of connectivity. Immunostaining of axons revealed both motor and sensory origins of the axons found in the channels of the bridge. Extensive myelination was observed throughout the bridge at 6 months, with centrally located and peripheral channels seemingly myelinated by oligodendrocytes and Schwann cells, respectively. Chondroitin sulfate proteoglycan deposition was restricted to the edges of the bridge, was greatest at 1 week, and significantly decreased by 6 weeks. The dynamics of collagen I and IV, laminin, and fibronectin deposition varied with time. These studies demonstrate that the bridge structure can support substantial long-term axon growth and myelination with limited scar formation.

  19. Long-Term Characterization of Axon Regeneration and Matrix Changes Using Multiple Channel Bridges for Spinal Cord Regeneration

    PubMed Central

    Tuinstra, Hannah M.; Margul, Daniel J.; Goodman, Ashley G.; Boehler, Ryan M.; Holland, Samantha J.; Zelivyanskaya, Marina L.; Cummings, Brian J.; Anderson, Aileen J.

    2014-01-01

    Spinal cord injury (SCI) results in loss of sensory and motor function below the level of injury and has limited available therapies. The host response to SCI is typified by limited endogenous repair, and biomaterial bridges offer the potential to alter the microenvironment to promote regeneration. Porous multiple channel bridges implanted into the injury provide stability to limit secondary damage and support cell infiltration that limits cavity formation. At the same time, the channels provide a path that physically directs axon growth across the injury. Using a rat spinal cord hemisection injury model, we investigated the dynamics of axon growth, myelination, and scar formation within and around the bridge in vivo for 6 months, at which time the bridge has fully degraded. Axons grew into and through the channels, and the density increased overtime, resulting in the greatest axon density at 6 months postimplantation, despite complete degradation of the bridge by that time point. Furthermore, the persistence of these axons contrasts with reports of axonal dieback in other models and is consistent with axon stability resulting from some degree of connectivity. Immunostaining of axons revealed both motor and sensory origins of the axons found in the channels of the bridge. Extensive myelination was observed throughout the bridge at 6 months, with centrally located and peripheral channels seemingly myelinated by oligodendrocytes and Schwann cells, respectively. Chondroitin sulfate proteoglycan deposition was restricted to the edges of the bridge, was greatest at 1 week, and significantly decreased by 6 weeks. The dynamics of collagen I and IV, laminin, and fibronectin deposition varied with time. These studies demonstrate that the bridge structure can support substantial long-term axon growth and myelination with limited scar formation. PMID:24168314

  20. Symptom profiles in the painDETECT Questionnaire in patients with peripheral neuropathic pain stratified according to sensory loss in quantitative sensory testing.

    PubMed

    Vollert, Jan; Kramer, Martin; Barroso, Alejandro; Freynhagen, Rainer; Haanpää, Maija; Hansson, Per; Jensen, Troels S; Kuehler, Bianca M; Maier, Christoph; Mainka, Tina; Reimer, Maren; Segerdahl, Märta; Serra, Jordi; Solà, Romà; Tölle, Thomas R; Treede, Rolf-Detlef; Baron, Ralf

    2016-08-01

    The painDETECT Questionnaire (PDQ) is commonly used as a screening tool to discriminate between neuropathic pain (NP) and nociceptive pain, based on the self-report of symptoms, including pain qualities, numbness, and pain to touch, cold, or heat. However, there are minimal data about whether the PDQ is differentially sensitive to different sensory phenotypes in NP. The aim of the study was to analyze whether the overall PDQ score or its items reflect phenotypes of sensory loss in NP as determined by quantitative sensory testing. An exploratory analysis in the Innovative Medicines Initiative Europain and Neuropain database was performed. Data records of 336 patients identified with NP were grouped into sensory profiles characterized by (1) no loss of sensation, (2) loss of thermal sensation, (3) loss of mechanical sensation, and (4) loss of thermal and mechanical sensation. painDETECT Questionnaire profiles were analyzed in a 2-factor analysis of variance. Patients with loss of thermal sensation (2 and 4) significantly more often reported pain evoked by light touch, and patients with loss of mechanical sensation (3 and 4) significantly more often reported numbness and significantly less often burning sensations and pain evoked by light touch. Although the PDQ was not designed to assess sensory loss, single items reflect thermal and/or mechanical sensory loss at group level, but because of substantial variability, the PDQ does not allow for individual allocation of patients into sensory profiles. It will be useful to develop screening tools according to the current definition of NP.

  1. Schwann cell interactions with axons and microvessels in diabetic neuropathy.

    PubMed

    Gonçalves, Nádia P; Vægter, Christian B; Andersen, Henning; Østergaard, Leif; Calcutt, Nigel A; Jensen, Troels S

    2017-03-01

    The prevalence of diabetes worldwide is at pandemic levels, with the number of patients increasing by 5% annually. The most common complication of diabetes is peripheral neuropathy, which has a prevalence as high as 50% and is characterized by damage to neurons, Schwann cells and blood vessels within the nerve. The pathogenic mechanisms of diabetic neuropathy remain poorly understood, impeding the development of targeted therapies to treat nerve degeneration and its most disruptive consequences of sensory loss and neuropathic pain. Involvement of Schwann cells has long been proposed, and new research techniques are beginning to unravel a complex interplay between these cells, axons and microvessels that is compromised during the development of diabetic neuropathy. In this Review, we discuss the evolving concept of Schwannopathy as an integral factor in the pathogenesis of diabetic neuropathy, and how disruption of the interactions between Schwann cells, axons and microvessels contribute to the disease.

  2. Diagnostic approach to peripheral neuropathy

    PubMed Central

    Misra, Usha Kant; Kalita, Jayantee; Nair, Pradeep P.

    2008-01-01

    Peripheral neuropathy refers to disorders of the peripheral nervous system. They have numerous causes and diverse presentations; hence, a systematic and logical approach is needed for cost-effective diagnosis, especially of treatable neuropathies. A detailed history of symptoms, family and occupational history should be obtained. General and systemic examinations provide valuable clues. Neurological examinations investigating sensory, motor and autonomic signs help to define the topography and nature of neuropathy. Large fiber neuropathy manifests with the loss of joint position and vibration sense and sensory ataxia, whereas small fiber neuropathy manifests with the impairment of pain, temperature and autonomic functions. Electrodiagnostic (EDx) tests include sensory, motor nerve conduction, F response, H reflex and needle electromyography (EMG). EDx helps in documenting the extent of sensory motor deficits, categorizing demyelinating (prolonged terminal latency, slowing of nerve conduction velocity, dispersion and conduction block) and axonal (marginal slowing of nerve conduction and small compound muscle or sensory action potential and dennervation on EMG). Uniform demyelinating features are suggestive of hereditary demyelination, whereas difference between nerves and segments of the same nerve favor acquired demyelination. Finally, neuropathy is classified into mononeuropathy commonly due to entrapment or trauma; mononeuropathy multiplex commonly due to leprosy and vasculitis; and polyneuropathy due to systemic, metabolic or toxic etiology. Laboratory investigations are carried out as indicated and specialized tests such as biochemical, immunological, genetic studies, cerebrospinal fluid (CSF) examination and nerve biopsy are carried out in selected patients. Approximately 20% patients with neuropathy remain undiagnosed but the prognosis is not bad in them. PMID:19893645

  3. Neurotoxic mechanisms of paclitaxel are local to the distal axon and independent of transport defects.

    PubMed

    Gornstein, Erica L; Schwarz, Thomas L

    2017-02-01

    Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side effect of paclitaxel and other chemotherapeutic agents. Paclitaxel binds and stabilizes microtubules, but the cellular mechanisms that underlie paclitaxel's neurotoxic effects are not well understood. We therefore used primary cultures of adult murine dorsal root ganglion neurons, the cell type affected in patients, to examine leading hypotheses to explain paclitaxel neurotoxicity. We address the role of microtubule hyperstabilization and its downstream effects. Paclitaxel administered at 10-50nM for 1-3days induced retraction bulbs at the tips of axons and arrested axon growth without triggering axon fragmentation or cell death. By correlating the toxic effects and microtubule stabilizing activity of structurally different microtubule stabilizing compounds, we confirmed that microtubule hyperstabilization, rather than an off-target effect, is the likely primary cause of paclitaxel neurotoxicity. We examined potential downstream consequences of microtubule hyperstabilization and found that changes in levels of tubulin posttranslational modifications, although present after paclitaxel exposure, are not implicated in the paclitaxel neurotoxicity we observed in the cultures. Additionally, defects in axonal transport were not implicated as an early, causative mechanism of paclitaxel's toxic effects on dorsal root ganglion neurons. By using microfluidic chambers to selectively treat different parts of the axon with paclitaxel, we found that the distal axon was primarily vulnerable to paclitaxel, indicating that paclitaxel acts directly on the distal axon to induce degenerative effects. Together, our findings point to local effects of microtubule hyperstabilization on the distal-most portion of the axon as an early mediator of paclitaxel neurotoxicity. Because sensory neurons have a unique and ongoing requirement for distal growth in order to reinnervate the epidermis as it turns over, we propose

  4. Afferent Fiber Remodeling in the Somatosensory Thalamus of Mice as a Neural Basis of Somatotopic Reorganization in the Brain and Ectopic Mechanical Hypersensitivity after Peripheral Sensory Nerve Injury

    PubMed Central

    Yagasaki, Yuki; Katayama, Yoko

    2017-01-01

    Abstract Plastic changes in the CNS in response to peripheral sensory nerve injury are a series of complex processes, ranging from local circuit remodeling to somatotopic reorganization. However, the link between circuit remodeling and somatotopic reorganization remains unclear. We have previously reported that transection of the primary whisker sensory nerve causes the abnormal rewiring of lemniscal fibers (sensory afferents) on a neuron in the mouse whisker sensory thalamus (V2 VPM). In the present study, using transgenic mice whose lemniscal fibers originate from the whisker sensory principle trigeminal nucleus (PrV2) are specifically labeled, we identified that the transection induced retraction of PrV2-originating lemniscal fibers and invasion of those not originating from PrV2 in the V2 VPM. This anatomical remodeling with somatotopic reorganization was highly correlated with the rewiring of lemniscal fibers. Origins of the non-PrV2-origin lemniscal fibers in the V2 VPM included the mandibular subregion of trigeminal nuclei and the dorsal column nuclei (DCNs), which normally represent body parts other than whiskers. The transection also resulted in ectopic receptive fields of V2 VPM neurons and extraterritorial pain behavior on the uninjured mandibular region of the face. The anatomical remodeling, emergence of ectopic receptive fields, and extraterritorial pain behavior all concomitantly developed within a week and lasted more than three months after the transection. Our findings, thus, indicate a strong linkage between these plastic changes after peripheral sensory nerve injury, which may provide a neural circuit basis underlying large-scale reorganization of somatotopic representation and abnormal ectopic sensations. PMID:28396882

  5. PI3K-GSK3 signalling regulates mammalian axon regeneration by inducing the expression of Smad1

    NASA Astrophysics Data System (ADS)

    Saijilafu; Hur, Eun-Mi; Liu, Chang-Mei; Jiao, Zhongxian; Xu, Wen-Lin; Zhou, Feng-Quan

    2013-10-01

    In contrast to neurons in the central nervous system, mature neurons in the mammalian peripheral nervous system (PNS) can regenerate axons after injury, in part, by enhancing intrinsic growth competence. However, the signalling pathways that enhance the growth potential and induce spontaneous axon regeneration remain poorly understood. Here we reveal that phosphatidylinositol 3-kinase (PI3K) signalling is activated in response to peripheral axotomy and that PI3K pathway is required for sensory axon regeneration. Moreover, we show that glycogen synthase kinase 3 (GSK3), rather than mammalian target of rapamycin, mediates PI3K-dependent augmentation of the growth potential in the PNS. Furthermore, we show that PI3K-GSK3 signal is conveyed by the induction of a transcription factor Smad1 and that acute depletion of Smad1 in adult mice prevents axon regeneration in vivo. Together, these results suggest PI3K-GSK3-Smad1 signalling as a central module for promoting sensory axon regeneration in the mammalian nervous system.

  6. Reversible acute axonal polyneuropathy associated with Wernicke-Korsakoff syndrome: impaired physiological nerve conduction due to thiamine deficiency?

    PubMed

    Ishibashi, S; Yokota, T; Shiojiri, T; Matunaga, T; Tanaka, H; Nishina, K; Hirota, H; Inaba, A; Yamada, M; Kanda, T; Mizusawa, H

    2003-05-01

    Acute axonal polyneuropathy and Wernicke-Korsakoff encephalopathy developed simultaneously in three patients. Nerve conduction studies (NCS) detected markedly decreased compound muscle action potentials (CMAPs) and sensory nerve action potentials (SNAPs) with minimal conduction slowing; sympathetic skin responses (SSRs) were also notably decreased. Sural nerve biopsies showed only mild axonal degeneration with scattered myelin ovoid formation. The symptoms of neuropathy lessened within two weeks after an intravenous thiamine infusion. CMAPs, SNAPs, and SSRs also increased considerably. We suggest that this is a new type of peripheral nerve impairment: physiological conduction failure with minimal conduction delay due to thiamine deficiency.

  7. Expression patterns of Slit and Robo family members in adult mouse spinal cord and peripheral nervous system.

    PubMed

    Carr, Lauren; Parkinson, David B; Dun, Xin-Peng

    2017-01-01

    The secreted glycoproteins, Slit1-3, are classic axon guidance molecules that act as repulsive cues through their well characterised receptors Robo1-2 to allow precise axon pathfinding and neuronal migration. The expression patterns of Slit1-3 and Robo1-2 have been most characterized in the rodent developing nervous system and the adult brain, but little is known about their expression patterns in the adult rodent peripheral nervous system. Here, we report a detailed expression analysis of Slit1-3 and Robo1-2 in the adult mouse sciatic nerve as well as their expression in the nerve cell bodies within the ventral spinal cord (motor neurons) and dorsal root ganglion (sensory neurons). Our results show that, in the adult mouse peripheral nervous system, Slit1-3 and Robo1-2 are expressed in the cell bodies and axons of both motor and sensory neurons. While Slit1 and Robo2 are only expressed in peripheral axons and their cell bodies, Slit2, Slit3 and Robo1 are also expressed in satellite cells of the dorsal root ganglion, Schwann cells and fibroblasts of peripheral nerves. In addition to these expression patterns, we also demonstrate the expression of Robo1 in blood vessels of the peripheral nerves. Our work gives important new data on the expression patterns of Slit and Robo family members within the peripheral nervous system that may relate both to nerve homeostasis and the reaction of the peripheral nerves to injury.

  8. Altered potassium channel distribution and composition in myelinated axons suppresses hyperexcitability following injury

    PubMed Central

    Calvo, Margarita; Richards, Natalie; Schmid, Annina B; Barroso, Alejandro; Zhu, Lan; Ivulic, Dinka; Zhu, Ning; Anwandter, Philipp; Bhat, Manzoor A; Court, Felipe A; McMahon, Stephen B; Bennett, David LH

    2016-01-01

    Neuropathic pain following peripheral nerve injury is associated with hyperexcitability in damaged myelinated sensory axons, which begins to normalise over time. We investigated the composition and distribution of shaker-type-potassium channels (Kv1 channels) within the nodal complex of myelinated axons following injury. At the neuroma that forms after damage, expression of Kv1.1 and 1.2 (normally localised to the juxtaparanode) was markedly decreased. In contrast Kv1.4 and 1.6, which were hardly detectable in the naïve state, showed increased expression within juxtaparanodes and paranodes following injury, both in rats and humans. Within the dorsal root (a site remote from injury) we noted a redistribution of Kv1-channels towards the paranode. Blockade of Kv1 channels with α-DTX after injury reinstated hyperexcitability of A-fibre axons and enhanced mechanosensitivity. Changes in the molecular composition and distribution of axonal Kv1 channels, therefore represents a protective mechanism to suppress the hyperexcitability of myelinated sensory axons that follows nerve injury. DOI: http://dx.doi.org/10.7554/eLife.12661.001 PMID:27033551

  9. Altered potassium channel distribution and composition in myelinated axons suppresses hyperexcitability following injury.

    PubMed

    Calvo, Margarita; Richards, Natalie; Schmid, Annina B; Barroso, Alejandro; Zhu, Lan; Ivulic, Dinka; Zhu, Ning; Anwandter, Philipp; Bhat, Manzoor A; Court, Felipe A; McMahon, Stephen B; Bennett, David L H

    2016-04-19

    Neuropathic pain following peripheral nerve injury is associated with hyperexcitability in damaged myelinated sensory axons, which begins to normalise over time. We investigated the composition and distribution of shaker-type-potassium channels (Kv1 channels) within the nodal complex of myelinated axons following injury. At the neuroma that forms after damage, expression of Kv1.1 and 1.2 (normally localised to the juxtaparanode) was markedly decreased. In contrast Kv1.4 and 1.6, which were hardly detectable in the naïve state, showed increased expression within juxtaparanodes and paranodes following injury, both in rats and humans. Within the dorsal root (a site remote from injury) we noted a redistribution of Kv1-channels towards the paranode. Blockade of Kv1 channels with α-DTX after injury reinstated hyperexcitability of A-fibre axons and enhanced mechanosensitivity. Changes in the molecular composition and distribution of axonal Kv1 channels, therefore represents a protective mechanism to suppress the hyperexcitability of myelinated sensory axons that follows nerve injury.

  10. Physician-assessed and patient-reported outcome measures in chemotherapy-induced sensory peripheral neurotoxicity: two sides of the same coin.

    PubMed

    Alberti, P; Rossi, E; Cornblath, D R; Merkies, I S J; Postma, T J; Frigeni, B; Bruna, J; Velasco, R; Argyriou, A A; Kalofonos, H P; Psimaras, D; Ricard, D; Pace, A; Galiè, E; Briani, C; Dalla Torre, C; Faber, C G; Lalisang, R I; Boogerd, W; Brandsma, D; Koeppen, S; Hense, J; Storey, D; Kerrigan, S; Schenone, A; Fabbri, S; Valsecchi, M G; Cavaletti, G

    2014-01-01

    The different perception and assessment of chemotherapy-induced peripheral neurotoxicity (CIPN) between healthcare providers and patients has not yet been fully addressed, although these two approaches might eventually lead to inconsistent, possibly conflicting interpretation, especially regarding sensory impairment. A cohort of 281 subjects with stable CIPN was evaluated with the National Cancer Institute-Common Toxicity Criteria (NCI-CTC v. 2.0) sensory scale, the clinical Total Neuropathy Score (TNSc©), the modified Inflammatory Neuropathy Cause and Treatment (INCAT) sensory sumscore (mISS) and the European Organization for Research and Treatment of Cancer CIPN specific self-report questionnaire (EORTC QOL-CIPN20). Patients' probability estimates showed that the EORTC QLQ-CIPN20 sensory score was overall more highly related to the NCI-CTC sensory score. However, the vibration perception item of the TNSc had a higher probability to be scored 0 for EORTC QLQ-CIPN20 scores lower than 35, as vibration score 2 for EORTC QLQ-CIPN20 scores between 35 and 50 and as grade 3 or 4 for EORTC QLQ-CIPN20 scores higher than 50. The linear models showed a significant trend between each mISS item and increasing EORTC QLQ-CIPN20 sensory scores. None of the clinical items had a perfect relationship with patients' perception, and most of the discrepancies stood in the intermediate levels of CIPN severity. Our data indicate that to achieve a comprehensive knowledge of CIPN including a reliable assessment of both the severity and the quality of CIPN-related sensory impairment, clinical and PRO measures should be always combined.

  11. Physician-assessed and patient-reported outcome measures in chemotherapy-induced sensory peripheral neurotoxicity: two sides of the same coin

    PubMed Central

    Alberti, P.; Rossi, E.; Cornblath, D. R.; Merkies, I. S. J.; Postma, T. J.; Frigeni, B.; Bruna, J.; Velasco, R.; Argyriou, A. A.; Kalofonos, H. P.; Psimaras, D.; Ricard, D.; Pace, A.; Galiè, E.; Briani, C.; Dalla Torre, C.; Faber, C. G.; Lalisang, R. I.; Boogerd, W.; Brandsma, D.; Koeppen, S.; Hense, J.; Storey, D.; Kerrigan, S.; Schenone, A.; Fabbri, S.; Valsecchi, M. G.; Cavaletti, G.; Cavaletti, G.; Cornblath, D.R.; Merkies, I.S.J.; Postma, T.J.; Valsecchi, M.G; Galimberti, S.; Rossi, E.; Cavaletti, G.; Frigeni, B.; Lanzani, F.; Mattavelli, L.; Piatti, ML.; Alberti, P.; Binda, D.; Bidoli, P..; Cazzaniga, M.; Cortinovis, D.; Bruna, J.; Velasco, R.; Argyriou, AA.; Kalofonos, HP.; Psimaras, D.; Ricard, D.; Pace, A.; Galiè, E.; Briani, C.; Lucchetta, M.; Campagnolo, M.; Dalla Torre, C.; Merkies, ISJ.; Faber, CG.; Merkies, ISJ.; Vanhoutte, EK.; Bakkers, M.; Brouwer, B.; Lalisang, RI.; Boogerd, W.; Brandsma, D.; Koeppen, S.; Hense, J.; Grant, R.; Storey, D.; Kerrigan, S.; Schenone, A.; Reni, L.; Piras, B.; Fabbri, S.; Padua, L.; Granata, G.; Leandri, M.; Ghignotti, I.; Plasmati, R..; Pastorelli, F.; Postma, TJ.; Heimans, JJ.; Eurelings, M.; Meijer, RJ.; Grisold, W.; Lindeck Pozza, E.; Mazzeo, A.; Toscano, A.; Tomasello, C.; Altavilla, G.; Penas Prado, M.; Dominguez Gonzalez, C.; Dorsey, SG.; Brell, JM.

    2014-01-01

    Background The different perception and assessment of chemotherapy-induced peripheral neurotoxicity (CIPN) between healthcare providers and patients has not yet been fully addressed, although these two approaches might eventually lead to inconsistent, possibly conflicting interpretation, especially regarding sensory impairment. Patients and methods A cohort of 281 subjects with stable CIPN was evaluated with the National Cancer Institute—Common Toxicity Criteria (NCI-CTC v. 2.0) sensory scale, the clinical Total Neuropathy Score (TNSc©), the modified Inflammatory Neuropathy Cause and Treatment (INCAT) sensory sumscore (mISS) and the European Organization for Research and Treatment of Cancer CIPN specific self-report questionnaire (EORTC QOL-CIPN20). Results Patients' probability estimates showed that the EORTC QLQ-CIPN20 sensory score was overall more highly related to the NCI-CTC sensory score. However, the vibration perception item of the TNSc had a higher probability to be scored 0 for EORTC QLQ-CIPN20 scores lower than 35, as vibration score 2 for EORTC QLQ-CIPN20 scores between 35 and 50 and as grade 3 or 4 for EORTC QLQ-CIPN20 scores higher than 50. The linear models showed a significant trend between each mISS item and increasing EORTC QLQ-CIPN20 sensory scores. Conclusion None of the clinical items had a perfect relationship with patients' perception, and most of the discrepancies stood in the intermediate levels of CIPN severity. Our data indicate that to achieve a comprehensive knowledge of CIPN including a reliable assessment of both the severity and the quality of CIPN-related sensory impairment, clinical and PRO measures should be always combined. PMID:24256846

  12. Genetic axonal neuropathies and neuronopathies of pre-natal and infantile onset.

    PubMed

    Yiu, Eppie M; Ryan, Monique M

    2012-09-01

    The infantile-onset axonal neuropathies and neuronopathies are an uncommon and heterogeneous group of conditions causing weakness, wasting, and developmental delay in early childhood. Many are associated with central nervous system or other systemic manifestations and cause early mortality. We review the axonal Charcot-Marie-Tooth subtypes with onset in infancy, spinal muscular atrophy, and related syndromes of early infancy, giant axonal neuropathy, infantile neuroaxonal dystrophy, hereditary motor and sensory neuropathy with agenesis of the corpus callosum, early-onset neuropathies associated with mitochondrial disorders, and other less well-delineated clinical entities. Useful clinical and neuropathologic features in the diagnostic work-up of these conditions are also presented. © 2012 Peripheral Nerve Society.

  13. Rodent models of chemotherapy-induced peripheral neuropathy.

    PubMed

    Höke, Ahmet; Ray, Mitali

    2014-01-01

    Peripheral neuropathy is a common and dose-limiting side effect of many chemotherapeutic drugs. These include platinum compounds, taxanes, vinca alkaloids, proteasome inhibitors, and others such as thalidomide and suramin. Although many rodent models have been developed using either mice or rats, there is limited consistency in the dose or mode of delivery of the drug; the sex, age, and genetic background of the animal used in the study; and the outcome measures used in evaluation of the peripheral neuropathy. Behavioral assays are commonly used to evaluate evoked sensory responses but are unlikely to be a good representation of the spontaneous sensory paresthesias that the patients experience. Electrophysiologic tests evaluate the integrity of large myelinated populations and are useful in drugs that cause either demyelination or degeneration of large myelinated axons but are insensitive to degeneration of unmyelinated axons in early stages of neuropathy. Histopathologic tools offer an unbiased way to evaluate the degree of axonal degeneration or changes in neuronal cell body but are often time consuming and require processing of the tissue after the study is completed. Nevertheless, use of drug doses and mode of delivery that are relevant to the clinical protocols and use of outcome measures that are both sensitive and objective in evaluation of the length-dependent distal axonal degeneration seen in most chemotherapy-induced peripheral neuropathies may improve the translational utility of these rodent models.

  14. Mitochondrial dynamics and peripheral neuropathy.

    PubMed

    Baloh, Robert H

    2008-02-01

    Peripheral neuropathy is perhaps the archetypal disease of axonal degeneration, characteristically involving degeneration of the longest axons in the body. Evidence from both inherited and acquired forms of peripheral neuropathy strongly supports that the primary pathology is in the axons themselves and points to disruption of axonal transport as an important disease mechanism. Recent studies in human genetics have further identified abnormalities in mitochondrial dynamics--the fusion, fission, and movement of mitochondria--as a player in the pathogenesis of inherited peripheral neuropathy. This review provides an update on the mechanisms of mitochondrial trafficking in axons and the emerging relationship between the disruption of mitochondrial dynamics and axonal degeneration. Evidence suggests mitochondria are a "critical cargo" whose transport is necessary for proper axonal and synaptic function. Importantly, understanding the regulation of mitochondrial movement and the consequences of decreased axonal mitochondrial function may define new paths for therapeutic agents in peripheral neuropathy and other neurodegenerative diseases.

  15. Impaired Axonal Regeneration in Diabetes. Perspective on the Underlying Mechanism from In Vivo and In Vitro Experimental Studies

    PubMed Central

    Sango, Kazunori; Mizukami, Hiroki; Horie, Hidenori; Yagihashi, Soroku

    2017-01-01

    Axonal regeneration after peripheral nerve injury is impaired in diabetes, but its precise mechanisms have not been elucidated. In this paper, we summarize the progress of research on altered axonal regeneration in animal models of diabetes and cultured nerve tissues exposed to hyperglycemia. Impaired nerve regeneration in animal diabetes can be attributed to dysfunction of neurons and Schwann cells, unfavorable stromal environment supportive of regenerating axons, and alterations of target tissues receptive to reinnervation. In particular, there are a number of factors such as enhanced activity of the negative regulators of axonal regeneration (e.g., phosphatase and tensin homolog deleted on chromosome 10 and Rho/Rho kinase), delayed Wallerian degeneration, alterations of the extracellular matrix components, enhanced binding of advanced glycation endproducts (AGEs) with the receptor for AGE, and delayed muscle reinnervation that can be obstacles to functional recovery after an axonal injury. It is also noteworthy that we and others have observed excessive neurite outgrowth from peripheral sensory ganglion explants from streptozotocin (STZ)-diabetic mice in culture and enhanced regeneration of small nerve fibers after sciatic nerve injury in STZ-induced diabetic rats. The excess of abortive neurite outgrowth may lead to misconnections of axons and target organs, which may interfere with appropriate target reinnervation and functional repair. Amelioration of perturbed nerve regeneration may be crucial for the future management of diabetic neuropathy. PMID:28203223

  16. Limited availability of ZBP1 restricts axonal mRNA localization and nerve regeneration capacity.

    PubMed

    Donnelly, Christopher J; Willis, Dianna E; Xu, Mei; Tep, Chhavy; Jiang, Chunsu; Yoo, Soonmoon; Schanen, N Carolyn; Kirn-Safran, Catherine B; van Minnen, Jan; English, Arthur; Yoon, Sung Ok; Bassell, Gary J; Twiss, Jeffery L

    2011-09-30

    Subcellular localization of mRNAs is regulated by RNA-protein interactions. Here, we show that introduction of a reporter mRNA with the 3'UTR of β-actin mRNA competes with endogenous mRNAs for binding to ZBP1 in adult sensory neurons. ZBP1 is needed for axonal localization of β-actin mRNA, and introducing GFP with the 3'UTR of β-actin mRNA depletes axons of endogenous β-actin and GAP-43 mRNAs and attenuates both in vitro and in vivo regrowth of severed axons. Consistent with limited levels of ZBP1 protein in adult neurons, mice heterozygous for the ZBP1 gene are haploinsufficient for axonal transport of β-actin and GAP-43 mRNAs and for regeneration of peripheral nerve. Exogenous ZBP1 can rescue the RNA transport deficits, but the axonal growth deficit is only rescued if the transported mRNAs are locally translated. These data support a direct role for ZBP1 in transport and translation of mRNA cargos in axonal regeneration in vitro and in vivo.

  17. Peripheral nerve injury modulates neurotrophin signaling in the peripheral and central nervous system.

    PubMed

    Richner, Mette; Ulrichsen, Maj; Elmegaard, Siri Lander; Dieu, Ruthe; Pallesen, Lone Tjener; Vaegter, Christian Bjerggaard

    2014-12-01

    Peripheral nerve injury disrupts the normal functions of sensory and motor neurons by damaging the integrity of axons and Schwann cells. In contrast to the central nervous system, the peripheral nervous system possesses a considerable capacity for regrowth, but regeneration is far from complete and functional recovery rarely returns to pre-injury levels. During development, the peripheral nervous system strongly depends upon trophic stimulation for neuronal differentiation, growth and maturation. The perhaps most important group of trophic substances in this context is the neurotrophins (NGF, BDNF, NT-3 and NT-4/5), which signal in a complex spatial and timely manner via the two structurally unrelated p75(NTR) and tropomyosin receptor kinase (TrkA, Trk-B and Trk-C) receptors. Damage to the adult peripheral nerves induces cellular mechanisms resembling those active during development, resulting in a rapid and robust increase in the synthesis of neurotrophins in neurons and Schwann cells, guiding and supporting regeneration. Furthermore, the injury induces neurotrophin-mediated changes in the dorsal root ganglia and in the spinal cord, which affect the modulation of afferent sensory signaling and eventually may contribute to the development of neuropathic pain. The focus of this review is on the expression patterns of neurotrophins and their receptors in neurons and glial cells of the peripheral nervous system and the spinal cord. Furthermore, injury-induced changes of expression patterns and the functional consequences in relation to axonal growth and remyelination as well as to neuropathic pain development will be reviewed.

  18. Functional recovery of denervated skeletal muscle with sensory or mixed nerve protection: a pilot study.

    PubMed

    Li, Qing Tian; Zhang, Pei Xun; Yin, Xiao Feng; Han, Na; Kou, Yu Hui; Deng, Jiu Xu; Jiang, Bao Guo

    2013-01-01

    Functional recovery is usually poor following peripheral nerve injury when reinnervation is delayed. Early innervation by sensory nerve has been indicated to prevent atrophy of the denervated muscle. It is hypothesized that early protection with sensory axons is adequate to improve functional recovery of skeletal muscle following prolonged denervation of mixed nerve injury. In this study, four groups of rats received surgical denervation of the tibial nerve. The proximal and distal stumps of the tibial nerve were ligated in all animals except for those in the immediate repair group. The experimental groups underwent denervation with nerve protection of peroneal nerve (mixed protection) or sural nerve (sensory protection). The experimental and unprotected groups had a stage II surgery in which the trimmed proximal and distal tibial nerve stumps were sutured together. After 3 months of recovery, electrophysiological, histological and morphometric parameters were assessed. It was detected that the significant muscle atrophy and a good preserved structure of the muscle were observed in the unprotected and protective experimental groups, respectively. Significantly fewer numbers of regenerated myelinated axons were observed in the sensory-protected group. Enhanced recovery in the mixed protection group was indicated by the results of the muscle contraction force tests, regenerated myelinated fiber, and the results of the histological analysis. Our results suggest that early axons protection by mixed nerve may complement sensory axons which are required for promoting functional recovery of the denervated muscle natively innervated by mixed nerve.

  19. Accommodation to hyperpolarizing currents: differences between motor and sensory nerves in mice.

    PubMed

    Nodera, Hiroyuki; Rutkove, Seward B

    2012-06-19

    Peripheral motor nerves have revealed variability in excitability by hyperpolarizing current at specific target response levels, likely reflecting differences in the hyperpolarization-activated current (Ih). Whether such variability in Ih exists in sensory axons is yet to be established. We performed nerve excitability testing in mouse tail motor and sensory nerves at 3 target response levels (20, 40, and 60% of the maximum amplitudes). Target-level dependent variability was present by long hyperpolarizing currents in motor and sensory nerves in which the recording at the low target level showed smaller threshold changes than at the high target level. Other excitability measures, however, showed no variability. Furthermore, the accommodation by long, strong hyperpolarization revealed smaller S3 accommodation (threshold change between the maximum and at the end of the 200 ms conditioning pulse) at the low target response level in sensory axons, but not in motor axons. Variation in the kinetics of the subtypes of the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in motor and sensory axons is the most likely explanation for these findings. The present study has proposed that nerve excitability testing may provide a non-invasive means for the assessment of the different types of Ih in neurological disorders where HCN subtypes play unique pathophysiological roles.

  20. Hereditary sensory radicular neuropathy: defective neurogenic inflammation.

    PubMed

    Westerman, R A; Block, A; Nunn, A; Delaney, C A; Hahn, A; Dennett, X; Carr, R W

    1992-01-01

    Hereditary sensory radicular neuropathy exhibits autosomal dominant inheritance with complete penetrance in males and incomplete penetrance in females. Newer tests of small sensory nerve function were used in screening 8 family members aged between 14 and 66 years. All exhibited some frequent features of the disorder with an onset in the 2nd or 3rd decade, foot ulceration, foot callus, loss of pin prick, thermal and light touch sensation, and some reduction in vibration acuity and proprioception in the lower limbs. The hands were involved in 3 of 8, muscle involvement was present in 5 of 8, but deafness was not detected by audiometry. Nerve conduction velocity, sensory action potentials, latency and amplitude, thermal acuity, vibration acuity and axon reflex flares were measured in all patients. One sural nerve biopsy confirmed the presence of peripheral fibre loss in this predominantly sensory neuropathy. Chemically evoked axon reflex tests were used to evaluate the extent of primary sensory nerve fibre involvement. All patients were tested using a Moor MBF 3-D dual channel laser Doppler velocimeter. Acetylcholine or phenylephrine iontophoretically applied as 16 mC doses evoked absent or tiny axon reflexes in areas of impaired pin prick sensation. By contrast, direct microvascular dilator responses to nitroprusside (smooth muscle dependent) and acetylcholine (endothelium-dependent) were present but somewhat reduced in areas with defective neurogenic inflammation. These results differ significantly from the responses obtained in age-matched healthy controls (P < 0.05). Foot pressure analysis was performed for orthoses in 2 affected members with foot ulceration using the Musgrave Footprint system.(ABSTRACT TRUNCATED AT 250 WORDS)

  1. A co-culture microtunnel technique demonstrating a significant contribution of unmyelinated Schwann cells to the acceleration of axonal conduction in Schwann cell-regulated peripheral nerve development.

    PubMed

    Sakai, Koji; Shimba, Kenta; Kotani, Kiyoshi; Jimbo, Yasuhiko

    2017-08-14

    Schwann cells (SCs) contribute to the regulation of axonal conduction in a myelin-dependent and -independent manner. However, due to the lack of investigative techniques that are able to record axonal conduction under conditions that control the proliferation of specific SC types, little is known about the extent to which myelinated SCs (mSCs) and unmyelinated SCs (umSCs) modulate axonal conduction. In this study, a microtunnel-electrode approach was applied to a neuron/SC co-culture technique. Rat dorsal root ganglion neurons and SCs were co-cultured in a microtunnel-electrode device, which enabled recording of the conduction delay in multiple axons passing through microtunnels. Despite the absence of nuclei in the microtunnel when SCs were eliminated, cultured cells were densely packed and expressed S100 beta (an SC marker) at a rate of 96% in neuron/SC co-culture, indicating that SCs migrated into the microtunnel. In addition, supplementation with ascorbic acid after 6 days in vitro (DIV) successfully induced myelination from 22 DIV. Activity recording experiments indicated that the conduction delay decreased with culture length from 17 DIV in the neuron/SC co-culture but not in neuron monoculture. Interestingly, the SC-modulated shortening of conduction delay was attenuated at 17 DIV and 22 DIV by supplementing the culture medium with ascorbic acid and, at the same time, suppressing SC proliferation, suggesting that immature umSCs increased axonal conduction velocity in a cell density-dependent manner before the onset of myelination. These results suggest that this method is an effective tool for investigating the contributions of mSCs or umSCs to the regulation of axonal conduction.

  2. The critical period for peripheral specification of dorsal root ganglion neurons is related to the period of sensory neurogenesis

    SciTech Connect

    Smith, C.L. )

    1990-12-01

    Thoracic sensory neurons in bullfrog tadpoles can be induced to form connections typical of brachial sensory neurons by transplanting thoracic ganglia to the branchial level at stages when some thoracic sensory neurons already have formed connections. In order to find out how many postmitotic sensory neurons survive transplantation, ({sup 3}H)thymidine was administered to tadpoles in which thoracic ganglia were transplanted to the brachial level unilaterally at stages VII to IX. Between 16 and 37% of the neurons in transplanted ganglia were unlabeled, as compared to 46 to 60% in unoperated ganglia. Transplanted ganglia contained fewer unlabeled neurons than corresponding unoperated ganglia, indicating that transplantation caused degeneration of postmitotic neurons. Therefore, a large fraction of the neurons that formed connections typical of brachial sensory neurons probably differentiated while they were at the brachial level.

  3. Target-dependence of sensory neurons: an ultrastructural comparison of axotomised dorsal root ganglion neurons with allowed or denied reinnervation of peripheral targets.

    PubMed

    Johnson, I P; Sears, T A

    2013-01-03

    Evidence is emerging for a role of rough endoplasmic reticulum (RER) in the form of stress granules, the unfolded protein response and protein bodies in the response of neurons to injury and in neurodegenerative diseases. Here, we have studied the role of the peripheral target in regulating the RER and polyribosomes of Nissl bodies in axotomised adult cat dorsal root ganglion (DRG) neurons where axonal regeneration and peripheral target reinnervation was either allowed or denied. Retrograde labelling with horseradish peroxidise was used as an independent marker to enable selection of only those DRG neuronal cell bodies with axons in the injured intercostal nerves. Indications of polyribosomal dispersal were seen by 6h following axotomy, and by 24h the normal orderly arrangement of lamellae of RER in Nissl bodies had become disorganised. These ultrastructural changes preceded light microscopical chromatolysis by 1-3d. The retrograde response was maximal 8-32 d after axotomy. Clusters of debris-laden satellite cells/macrophages were present at this time but no ultrastructural evidence of neuronal apoptosis or necrosis was seen and there were no differences in the initial retrograde response according to the type of injury. By 64 d following axotomy with reinnervation, approximately half the labelled DRG neurons showed restoration of the orderly arrangement of RER and polyribosomes in their Nissl bodies. This was not seen after axotomy with reinnervation denied. We propose that the target-dependent changes in Nissl body ultrastructure described here are part of a continuum that can modify neuronal protein synthesis directed towards growth, maintenance or death of the neuron. This represents a possible structural basis for mediating the varied effects of neurotrophic interactions.

  4. Identification of the Ulex europaeus agglutinin-I-binding protein as a unique glycoform of the neural cell adhesion molecule in the olfactory sensory axons of adults rats.

    PubMed

    Pestean, A; Krizbai, I; Böttcher, H; Párducz, A; Joó, F; Wolff, J R

    1995-08-04

    Histochemical localization of two lectins, Ulex europaeus agglutinin-I (UEA-I) and Tetragonolobus purpureus (TPA), was studied in the olfactory bulb of adult rats. In contrast to TPA, UEA-I detected a fucosylated glycoprotein that is only present in the surface membranes of olfactory sensory cells including the whole course of their neurites up to the final arborization in glomeruli. Immunoblotting revealed that UEA-I binds specifically to a protein of 205 kDa, while TPA stains several other glycoproteins. Affinity chromatography with the use of a UEA-I column identified the 205 kDa protein as a glycoform of neural cell adhesion molecule (N-CAM), specific for the rat olfactory sensory nerves.

  5. Reduced evoked motor and sensory potential amplitudes in obstructive sleep apnea patients.

    PubMed

    Mihalj, Mario; Lušić, Linda; Đogaš, Zoran

    2016-06-01

    It is unknown to what extent chronic intermittent hypoxaemia in obstructive sleep apnea causes damage to the motor and sensory peripheral nerves. It was hypothesized that patients with obstructive sleep apnea would have bilaterally significantly impaired amplitudes of both motor and sensory peripheral nerve-evoked potentials of both lower and upper limbs. An observational study was conducted on 43 patients with obstructive sleep apnea confirmed by the whole-night polysomnography, and 40 controls to assess the relationship between obstructive sleep apnea and peripheral neuropathy. All obstructive sleep apnea subjects underwent standardized electroneurographic testing, with full assessment of amplitudes of evoked compound muscle action potentials, sensory neural action potentials, motor and sensory nerve conduction velocities, and distal motor and sensory latencies of the median, ulnar, peroneal and sural nerves, bilaterally. All nerve measurements were compared with reference values, as well as between the untreated patients with obstructive sleep apnea and control subjects. Averaged compound muscle action potential and sensory nerve action potential amplitudes were significantly reduced in the nerves of both upper and lower limbs in patients with obstructive sleep apnea compared with controls (P < 0.001). These results confirmed that patients with obstructive sleep apnea had significantly lower amplitudes of evoked action potentials of both motor and sensory peripheral nerves. Clinical/subclinical axonal damage exists in patients with obstructive sleep apnea to a greater extent than previously thought.

  6. Mitochondrial dynamics and inherited peripheral nerve diseases.

    PubMed

    Pareyson, Davide; Saveri, Paola; Sagnelli, Anna; Piscosquito, Giuseppe

    2015-06-02

    Peripheral nerves have peculiar energetic requirements because of considerable length of axons and therefore correct mitochondria functioning and distribution along nerves is fundamental. Mitochondrial dynamics refers to the continuous change in size, shape, and position of mitochondria within cells. Abnormalities of mitochondrial dynamics produced by mutations in proteins involved in mitochondrial fusion (mitofusin-2, MFN2), fission (ganglioside-induced differentiation-associated protein-1, GDAP1), and mitochondrial axonal transport usually present with a Charcot-Marie-Tooth disease (CMT) phenotype. MFN2 mutations cause CMT type 2A by altering mitochondrial fusion and trafficking along the axonal microtubule system. CMT2A is an axonal autosomal dominant CMT type which in most cases is characterized by early onset and rather severe course. GDAP1 mutations also alter fission, fusion and transport of mitochondria and are associated either with recessive demyelinating (CMT4A) and axonal CMT (AR-CMT2K) and, less commonly, with dominant, milder, axonal CMT (CMT2K). OPA1 (Optic Atrophy-1) is involved in fusion of mitochondrial inner membrane, and its heterozygous mutations lead to early-onset and progressive dominant optic atrophy which may be complicated by other neurological symptoms including peripheral neuropathy. Mutations in several proteins fundamental for the axonal transport or forming the axonal cytoskeleton result in peripheral neuropathy, i.e., CMT, distal hereditary motor neuropathy (dHMN) or hereditary sensory and autonomic neuropathy (HSAN), as well as in hereditary spastic paraplegia. Indeed, mitochondrial transport involves directly or indirectly components of the kinesin superfamily (KIF5A, KIF1A, KIF1B), responsible of anterograde transport, and of the dynein complex and related proteins (DYNC1H1, dynactin, dynamin-2), implicated in retrograde flow. Microtubules, neurofilaments, and chaperones such as heat shock proteins (HSPs) also have a fundamental

  7. Peripheral neuropathy in patients with myotonic dystrophy type 2.

    PubMed

    Leonardis, L

    2017-05-01

    Myotonic dystrophy type 2 (dystrophia myotonica type 2-DM2) is an autosomal dominant multi-organ disorder. The involvement of the peripheral nervous system was found in 25%-45% of patients with myotonic dystrophy type 1, although limited data are available concerning polyneuropathy in patients with DM2, which was the aim of this study with a thorough presentation of the cases with peripheral neuropathy. Patients with genetically confirmed DM2 underwent motor nerve conduction studies of the median, ulnar, tibial and fibular nerves and sensory nerve conduction studies of the median (second finger), ulnar (fifth finger), radial (forearm) and sural nerves. Seventeen adult patients with DM2 participated in the study. Fifty-three percent (9/17) of our patients had abnormality of one or more attributes (latency, amplitude or conduction velocity) in two or more separate nerves. Four types of neuropathies were found: (i) predominantly axonal motor and sensory polyneuropathy, (ii) motor polyneuropathy, (iii) predominantly demyelinating motor and sensory polyneuropathy and (iv) mutilating polyneuropathy with ulcers. The most common forms are axonal motor and sensory polyneuropathy (29%) and motor neuropathy (18% of all examined patients). No correlations were found between the presence of neuropathy and age, CCTG repeats, blood glucose or HbA1C. Peripheral neuropathy is common in patients with DM2 and presents one of the multisystemic manifestations of DM2. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  8. Acute transverse myelitis and acute motor axonal neuropathy developed after vaccinations against seasonal and 2009 A/H1N1 influenza.

    PubMed

    Sato, Nozomu; Watanabe, Kosuke; Ohta, Kiyobumi; Tanaka, Hiroaki

    2011-01-01

    Acute transverse myelitis (ATM) has been described as an uncommon complication of vaccinations and is rarely accompanied by inflammatory peripheral neuropathy. We report a case of a 77-year-old woman who developed ATM and acute motor axonal neuropathy (AMAN) following vaccinations against seasonal and 2009 A/H1N1 influenza. She manifested ophthalmoplegia, quadriparesis and sensory impairment. MR imaging showed a longitudinally-extensive spinal cord lesion, and nerve conduction study revealed motor axonal polyneuropathy. Despite prompt treatment, her symptoms poorly recovered. While concurrent ATM and AMAN may suggest the presence of a common antigen, their scarcity indicates the importance of other factors causing immunologic disruptions.

  9. Induction of monocyte chemoattractant protein-1 (MCP-1) and its receptor CCR2 in primary sensory neurons contributes to paclitaxel-induced peripheral neuropathy

    PubMed Central

    Zhang, Haijun; Boyette-Davis, Jessica A.; Kosturakis, Alyssa K.; Li, Yan; Yoon, Seo-Yeon; Walters, Edgar T.; Dougherty, Patrick M.

    2013-01-01

    The use of paclitaxel (Taxol®), a microtubule stabilizer, for cancer treatment is often limited by its associated peripheral neuropathy (chemotherapy-induced peripheral neuropathy, CIPN) which predominantly results in sensory dysfunction including chronic pain. Here we show that paclitaxel CIPN was associated with an induction of chemokine monocyte chemoattractant protein-1 (MCP-1) and its cognate receptor CCR2 in primary sensory neurons of dorsal root ganglia (DRG). Immunostaining revealed that MCP-1 was mainly expressed in small nociceptive neurons while CCR2 was expressed in large and medium-sized myelinated neurons. Direct application of MCP-1 consistently induced intracellular calcium increases in DRG large and medium-sized but not small neurons mainly dissociated from paclitaxel- but not vehicle-treated animals. Paclitaxel also induced increased expression of MCP-1 in spinal astrocytes but no CCR2 signal was detected in spinal cord. Local blockade of MCP-1/CCR2 signaling by anti-MCP-1 antibody or CCR2 antisense oligodeoxynucleotides significantly attenuated paclitaxel CIPN phenotypes including mechanical hypersensitivity and loss of intraepidermal nerve fibers (IENFs) in hindpaw glabrous skin. These results suggest that activation of paracrine MCP-1/CCR2 signaling between DRG neurons plays a critical role in the development of paclitaxel CIPN and targeting MCP-1/CCR2 signaling could be a novel therapeutic approach. PMID:23726937

  10. Synapse Plasticity in Motor, Sensory, and Limbo-Prefrontal Cortex Areas as Measured by Degrading Axon Terminals in an Environment Model of Gerbils (Meriones unguiculatus)

    PubMed Central

    Neufeld, Janina; Teuchert-Noodt, Gertraud; Grafen, Keren; Winter, York; Witte, A. Veronica

    2009-01-01

    Still little is known about naturally occurring synaptogenesis in the adult neocortex and related impacts of epigenetic influences. We therefore investigated (pre)synaptic plasticity in various cortices of adult rodents, visualized by secondary lysosome accumulations (LA) in remodeling axon terminals. Twenty-two male gerbils from either enriched (ER) or impoverished rearing (IR) were used for quantification of silver-stained LA. ER-animals showed rather low LA densities in most primary fields, whereas barrel and secondary/associative cortices exhibited higher densities and layer-specific differences. In IR-animals, these differences were evened out or even inverted. Basic plastic capacities might be linked with remodeling of local intrinsic circuits in the context of cortical map adaptation in both IR- and ER-animals. Frequently described disturbances due to IR in multiple corticocortical and extracortical afferent systems, including the mesocortical dopamine projection, might have led to maladaptations in the plastic capacities of prefronto-limbic areas, as indicated by different LA densities in IR- compared with ER-animals. PMID:19809517

  11. Peripheral competition in the control of sensory neuron numbers in Xenopus frogs reared with a single bilaterally innervated hindlimb.

    PubMed

    Lamb, A H; Ferns, M J; Klose, K

    1989-01-01

    Sensory neurons were counted in the hind-limb innervating spinal ganglia on both sides of juvenile Xenopus frogs which, as tadpoles, had had one hind limb bud amputated prior to innervation, and a channel made to allow innervation of the remaining limb bud from both sides. The total number of sensory neurons surviving on the two sides approximated the number on one side of normal frogs, the ipsilateral and contralateral numbers being negatively correlated. These effects differ markedly from the effects on motoneuron numbers, suggesting different control mechanisms of cell death in the two neuronal classes.

  12. Sensory cortex limits cortical maps and drives top-down plasticity in thalamocortical circuits

    PubMed Central

    Zembrzycki, Andreas; Chou, Shen-Ju; Ashery-Padan, Ruth; Stoykova, Anastassia; O’Leary, Dennis D.M.

    2013-01-01

    Summary Primary somatosensory cortex (S1) contains a complete body map that mirrors subcortical maps developed by peripheral sensory input projecting to sensory hindbrain, thalamus, then S1. Peripheral changes during development alter these maps through ‘bottom-up’ plasticity. Unknown is how S1 size influences map organization and if an altered S1 map feedbacks to affect subcortical maps. We show in mice that S1 is significantly reduced by cortex-specific deletion of Pax6, resulting in a reduced body map and loss of body representations by exclusion of later-differentiating sensory thalamocortical input. An initially normal sensory thalamus was re-patterned to match the aberrant S1 map by apoptotic deletion of thalamic neurons representing body parts with axons excluded from S1. Deleted representations were rescued by altering competition between thalamocortical axons by sensory deprivation or increasing S1. Thus, S1 size determined resolution and completeness of body maps and engaged ‘top-down’ plasticity that re-patterned sensory thalamus to match S1. PMID:23831966

  13. Mutations in the MORC2 gene cause axonal Charcot-Marie-Tooth disease.

    PubMed

    Sevilla, Teresa; Lupo, Vincenzo; Martínez-Rubio, Dolores; Sancho, Paula; Sivera, Rafael; Chumillas, María J; García-Romero, Mar; Pascual-Pascual, Samuel I; Muelas, Nuria; Dopazo, Joaquín; Vílchez, Juan J; Palau, Francesc; Espinós, Carmen

    2016-01-01

    Charcot-Marie-Tooth disease (CMT) is a complex disorder with wide genetic heterogeneity. Here we present a new axonal Charcot-Marie-Tooth disease form, associated with the gene microrchidia family CW-type zinc finger 2 (MORC2). Whole-exome sequencing in a family with autosomal dominant segregation identified the novel MORC2 p.R190W change in four patients. Further mutational screening in our axonal Charcot-Marie-Tooth disease clinical series detected two additional sporadic cases, one patient who also carried the same MORC2 p.R190W mutation and another patient that harboured a MORC2 p.S25L mutation. Genetic and in silico studies strongly supported the pathogenicity of these sequence variants. The phenotype was variable and included patients with congenital or infantile onset, as well as others whose symptoms started in the second decade. The patients with early onset developed a spinal muscular atrophy-like picture, whereas in the later onset cases, the initial symptoms were cramps, distal weakness and sensory impairment. Weakness and atrophy progressed in a random and asymmetric fashion and involved limb girdle muscles, leading to a severe incapacity in adulthood. Sensory loss was always prominent and proportional to disease severity. Electrophysiological studies were consistent with an asymmetric axonal motor and sensory neuropathy, while fasciculations and myokymia were recorded rather frequently by needle electromyography. Sural nerve biopsy revealed pronounced multifocal depletion of myelinated fibres with some regenerative clusters and occasional small onion bulbs. Morc2 is expressed in both axons and Schwann cells of mouse peripheral nerve. Different roles in biological processes have been described for MORC2. As the silencing of Charcot-Marie-Tooth disease genes have been associated with DNA damage response, it is tempting to speculate that a deregulation of this pathway may be linked to the axonal degeneration observed in MORC2 neuropathy, thus adding a

  14. Electrical stimulation promotes sensory neuron regeneration and growth-associated gene expression.

    PubMed

    Geremia, Nicole M; Gordon, Tessa; Brushart, Thomas M; Al-Majed, Abdulhakeem A; Verge, Valerie M K

    2007-06-01

    Brief electrical stimulation enhances the regenerative ability of axotomized motor [Nix, W.A., Hopf, H.C., 1983. Electrical stimulation of regenerating nerve and its effect on motor recovery. Brain Res. 272, 21-25; Al-Majed, A.A., Neumann, C.M., Brushart, T.M., Gordon, T., 2000. Brief electrical stimulation promotes the speed and accuracy of motor axonal regeneration. J. Neurosci. 20, 2602-2608] and sensory [Brushart, T.M., Jari, R., Verge, V., Rohde, C., Gordon, T., 2005. Electrical stimulation restores the specificity of sensory axon regeneration. Exp. Neurol. 194, 221-229] neurons. Here we examined the pa