Remodeling of lumbar motor circuitry remote to a thoracic spinal cord injury promotes locomotor recovery

Retrogradely-transported neurotrophin signaling plays an important role in regulating neural circuit specificity. Here we investigated whether targeted delivery of neurotrophin-3 (NT-3) to lumbar motoneurons (MNs) caudal to a thoracic (T10) contusive spinal cord injury (SCI) could modulate dendritic patterning and synapse formation of the lumbar MNs. In vitro, Adeno-associated virus serotype two overexpressing NT-3 (AAV-NT-3) induced NT-3 expression and neurite outgrowth in cultured spinal cord neurons. In vivo, targeted delivery of AAV-NT-3 into transiently demyelinated adult mouse sciatic nerves led to the retrograde transportation of NT-3 to the lumbar MNs, significantly attenuating SCI-induced lumbar MN dendritic atrophy. NT-3 enhanced sprouting and synaptic formation of descending serotonergic, dopaminergic, and propriospinal axons on lumbar MNs, parallel to improved behavioral recovery. Thus, retrogradely transported NT-3 stimulated remodeling of lumbar neural circuitry and synaptic connectivity remote to a thoracic SCI, supporting a role for retrograde transport of NT-3 as a potential therapeutic strategy for SCI.

• Publication year

  2018

• Venue

  eLife

• Publication date

  2018-09-12

• Fields of study

  Medicine

• Identifiers
  DOI 10.7554/eLife.39016PMID 30207538PMCID 6170189
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Gene Delivery

  2020cited by this paper
• RhoA/Rho Kinase Mediates Neuronal Death Through Regulating cPLA2 Activation

  2016cited by this paper
• A descending dopamine pathway conserved from basal vertebrates to mammals

  2016cited by this paper
• Treadmill training induced lumbar motoneuron dendritic plasticity and behavior recovery in adult rats after a thoracic contusive spinal cord injury.

  2015cited by this paper
• Activity dependent therapies modulate the spinal changes that motoneurons suffer after a peripheral nerve injury.

  2015cited by this paper
• A novel method for the measurement of hepatitis C virus infectious titres using the IncuCyte ZOOM and its application to antiviral screening

  2015cited by this paper
• Vector-induced NT-3 expression in rats promotes collateral growth of injured corticospinal tract axons far rostral to a spinal cord injury.

  2014cited by this paper
• Cytosolic Phospholipase A2 Protein as a Novel Therapeutic Target for Spinal Cord Injury

  2014cited by this paper
• Inhibition of Cytosolic Phospholipase A2 Has Neuroprotective Effects on Motoneuron and Muscle Atrophy after Spinal Cord Injury

  2014cited by this paper
• Dendrite morphogenesis depends on relative levels of NT-3/TrkC signaling

  2014cited by this paper
• Cytosolic Phospholipase A 2 Protein as a Novel Therapeutic Target for Spinal Cord Injury

  2014cited by this paper
• The integration of NSC-derived and host neural networks after rat spinal cord transection.

  2013cited by this paper
• A Novel Growth-Promoting Pathway Formed by GDNF-Overexpressing Schwann Cells Promotes Propriospinal Axonal Regeneration, Synapse Formation, and Partial Recovery of Function after Spinal Cord Injury

  2013cited by this paper
• A bilateral head injury that shows graded brain damage and behavioral deficits in adultmice.

  2013cited by this paper
• Combination of chondroitinase ABC and AAV-NT3 promotes neural plasticity at descending spinal pathways after thoracic contusion in rats.

  2013cited by this paper
• Enhancing Proprioceptive Input to Motoneurons Differentially Affects Expression of Neurotrophin 3 and Brain-Derived Neurotrophic Factor in Rat Hoffmann-Reflex Circuitry

  2013cited by this paper
• Neurotrophin regulation of neural circuit development and function

  2012cited by this paper
• Neuroprotective effects of testosterone on motoneuron and muscle morphology following spinal cord injury

  2012cited by this paper
• Retrograde neural circuit specification by target-derived neurotrophins and growth factors.

  2011cited by this paper
• Functional regeneration of respiratory pathways after spinal cord injury

  2011cited by this paper
• Neurotrophins: Potential Therapeutic Tools for the Treatment of Spinal Cord Injury

  2011cited by this paper
• Comparison of AAV2 and AAV5 in gene transfer in the injured spinal cord of mice

  2011cited by this paper
• Characterizing Phospholipase A2-Induced Spinal Cord Injury—A Comparison with Contusive Spinal Cord Injury in Adult Rats

  2011cited by this paper
• Intramuscular AAV delivery of NT‐3 alters synaptic transmission to motoneurons in adult rats

  2010cited by this paper
• Enhanced adenoviral gene delivery to motor and dorsal root ganglion neurons following injection into demyelinated peripheral nerves

  2010cited by this paper
• Sialidase enhances recovery from spinal cord contusion injury

  2010cited by this paper
• Transient demyelination increases the efficiency of retrograde AAV transduction.

  2010cited by this paper
• Strategies to restore motor functions after spinal cord injury.

  2009cited by this paper
• Chemotropic Guidance Facilitates Axonal Regeneration and Synapse Formation after Spinal Cord Injury

  2009cited by this paper
• Muscle Injection of AAV-NT3 Promotes Anatomical Reorganization of CST Axons and Improves Behavioral Outcome following SCI

  2009influential reference
• Gait Analysis in Normal and Spinal Contused Mice Using the TreadScan System

  2009cited by this paper
• Recovery of supraspinal control of stepping via indirect propriospinal relay connections after spinal cord injury

  2008cited by this paper
• Spinal Cord Contusion Based on Precise Vertebral Stabilization and Tissue Displacement Measured by Combined Assessment to Discriminate Small Functional Differences

  2008cited by this paper
• Repulsive Wnt Signaling Inhibits Axon Regeneration after CNS Injury

  2008cited by this paper
• Descending command systems for the initiation of locomotion in mammals.

  2008cited by this paper
• Inhibiting Epidermal Growth Factor Receptor Improves Structural, Locomotor, Sensory, and Bladder Recovery from Experimental Spinal Cord Injury

  2007cited by this paper
• Annexin A1 Reduces Inflammatory Reaction and Tissue Damage Through Inhibition of Phospholipase A2 Activation in Adult Rats Following Spinal Cord Injury

  2007cited by this paper
• Gene delivery to the spinal cord: Comparison between lentiviral, adenoviral, and retroviral vector delivery systems

  2006cited by this paper
• Methods for isolating highly-enriched embryonic spinal cord neurons: a comparison between enzymatic and mechanical dissociations.

  2006cited by this paper
• Basso Mouse Scale for Locomotion Detects Differences in Recovery after Spinal Cord Injury in Five Common Mouse Strains

  2006cited by this paper
• Chondroitinase ABC Promotes Sprouting of Intact and Injured Spinal Systems after Spinal Cord Injury

  2006cited by this paper
• A novel role of phospholipase A2 in mediating spinal cord secondary injury

  2006cited by this paper
• Regeneration of descending axon tracts after spinal cord injury.

  2005cited by this paper
• PKC mediates inhibitory effects of myelin and chondroitin sulfate proteoglycans on axonal regeneration

  2004cited by this paper
• Effects of limb exercise after spinal cord injury on motor neuron dendrite structure

  2004cited by this paper
• Passive exercise and fetal spinal cord transplant both help to restore motoneuronal properties after spinal cord transection in rats

  2004influential reference
• Spinal projections of the gigantocellular reticular formation in the rat. Evidence for projections from different areas to laminae I and II and lamina IX

  2004cited by this paper
• Neurotrophin-3 Expressed In Situ Induces Axonal Plasticity in the Adult Injured Spinal Cord

  2003cited by this paper
• Peripheral NT3 signaling is required for ETS protein expression and central patterning of proprioceptive sensory afferents.

  2003cited by this paper
• Changes in serotonin, serotonin transporter expression and serotonin denervation supersensitivity: involvement in chronic central pain after spinal hemisection in the rat.

  2002cited by this paper
• BRIEF COMMUNICATION Both Dorsal and Ventral Spinal Cord Pathways Contribute to Overground Locomotion in the Adult Rat

  2002cited by this paper
• Cervical sprouting of corticospinal fibers after thoracic spinal cord injury accompanies shifts in evoked motor responses.

  2001cited by this paper
• The Midbrain Dopaminergic System: Anatomy and Genetic Variation in Dopamine Neuron Number of Inbred Mouse Strains

  2001cited by this paper
• Physiological changes accompanying anatomical remodeling of mammalian motoneurons during postnatal development.

  2000cited by this paper
• Neurotrophin expression by spinal motoneurons in adult and developing rats

  2000cited by this paper
• Neurotrophins and trk-receptors in adult rat spinal motoneurons: differences related to cell size but not to 'slow/fast' specialization.

  2000cited by this paper
• Distinct populations of hypothalamic dopaminergic neurons exhibit differential responses to brain‐derived neurotrophic factor (BDNF) and neurotrophin‐3 (NT3)

  1999influential reference
• trkA, trkB, and trkC messenger RNA expression by bulbospinal cells of the rat.

  1999influential reference
• Distribution of 5‐hydroxytryptamine‐immunoreactive boutons on α‐motoneurons in the lumbar spinal cord of adult cats

  1998cited by this paper
• Cellular Delivery of Neurotrophin-3 Promotes Corticospinal Axonal Growth and Partial Functional Recovery after Spinal Cord Injury

  1997cited by this paper
• Neurotrophic factors increase axonal growth after spinal cord injury and transplantation in the adult rat.

  1997influential reference
• The synaptic drive from the spinal locomotor network to motoneurons in the newborn rat

  1996cited by this paper
• Localization and organization of the central pattern generator for hindlimb locomotion in newborn rat

  1995cited by this paper
• Neurotrophins regulate dendritic growth in developing visual cortex.

  1995cited by this paper
• Dopaminergic neurons in rat ventral midbrain express brain‐derived neurotrophic factor and neurotrophin‐3 mRNAs

  1994cited by this paper
• Lack of neurotrophin-3 leads to deficiencies in the peripheral nervous system and loss of limb proprioceptive afferents.

  1994cited by this paper
• The Trk family of neurotrophin receptors.

  1994cited by this paper
• Neurotrophin-3 enhances sprouting of corticospinal tract during development and after adult spinal cord lesion

  1994cited by this paper
• Overlapping and distinct actions of the neurotrophins BDNF, NT-3, and NT-4/5 on cultured dopaminergic and GABAergic neurons of the ventral mesencephalon

  1994cited by this paper
• Functions of the neurotrophins during nervous system development: what the knockouts are teaching us.

  1994cited by this paper
• Changes in dendritic morphology of rat spinal motoneurons during development and after unilateral target deletion.

  1993cited by this paper
• Neurotrophins promote motor neuron survival and are present in embryonic limb bud

  1993cited by this paper
• Molecular cloning of rat trkC and distribution of cells expressing messenger RNAs for members of the trk family in the rat central nervous system.

  1992cited by this paper
• Influence of spinal cord hemisection on the configurational changes in motor and primary afferent neurons and the chemical messenger alterations in the rat lumbar segments.

  1992cited by this paper
• Initiation and modulation of the locomotor pattern in the adult chronic spinal cat by noradrenergic, serotonergic and dopaminergic drugs.

  1991cited by this paper
• The efferent projections from the reticular formation and the locus coeruleus studied by anterograde and retrograde axonal transport in the rat

  1985cited by this paper
• Descending serotonergic, peptidergic and cholinergic pathways from the raphe nuclei: a multiple transmitter complex.

  1983cited by this paper

• POU6F1 promote lumbar motor circuit reorganization following spinal cord injury.

  2025cites this paper
• The Effect of Dopamine on Neuroplasticity in Spinal Cord Injury

  2025cites this paper
• Ngn2 and Isl1-mediated astrocyte-to-neuron conversion in vivo promotes functional recovery after spinal cord injury

  2025cites this paper
• Thoracic Spinal Cord Contusion Impacts on Lumbar Enlargement: Molecular Insights

  2025cites this paper
• Compensatory adaptation of parallel motor pathways promotes skilled forelimb recovery after spinal cord injury

  2024cites this paper
• Real-Time Analysis of Neuronal Cell Cultures for CNS Drug Discovery

  2024cites this paper
• Chondroitinase ABC combined with Schwann cell transplantation enhances restoration of neural connection and functional recovery following acute and chronic spinal cord injury

  2024cites this paper
• Nicotinamide Riboside Promotes the Proliferation of Endogenous Neural Stem Cells to Repair Spinal Cord Injury

  2024cites this paper
• Spinal Cord Transcutaneous Stimulation in Cervical Spinal Cord Injury: A Review Examining Upper Extremity Neuromotor Control, Recovery Mechanisms, and Future Directions

  2024cites this paper
• New strategy to treat spinal cord injury: Nafamostat mesilate suppressed NLRP3-mediated pyroptosis during acute phase.

  2024cites this paper
• Role of dendritic cells in spinal cord injury

  2024cites this paper
• Alleviating Severe Cytoskeletal Destruction of Spinal Motor Neurons: Another Effect of Docosahexaenoic Acid in Spinal Cord Injury.

  2024cites this paper
• Enhancement of motor functional recovery in thoracic spinal cord injury: voluntary wheel running versus forced treadmill exercise

  2024influential citation
• Expression of Parvalbumin, Osteopontin and Glypican 4 in Neurons of Lumbar Region Distant from the Epicenter of Traumatic Spinal Cord Injury

  2024cites this paper
• Advances in molecular therapies for targeting pathophysiology in spinal cord injury

  2023cites this paper
• Chemical conversion of human conventional PSCs to TSCs following transient naive gene activation

  2023cites this paper
• Enhanced axon outgrowth of spinal motor neurons in co-culturing with dorsal root ganglions antagonizes the growth inhibitory environment

  2023cites this paper
• Levels of neurotrophins in the brain of female rats in an experimental model of malignant tumor growth under conditions of hypothyroidism

  2023cites this paper
• RNA Sequencing and Spatial Transcriptomics in Traumatic Spinal Cord Injury (Review)

  2023cites this paper
• Schwann cell functions in peripheral nerve development and repair.

  2023cites this paper
• Delayed viral vector mediated delivery of neurotrophin-3 improves skilled hindlimb function and stability after thoracic contusion

  2022cites this paper
• Circuit reconstruction of newborn neurons after spinal cord injury in adult rats via an NT3-chitosan scaffold.

  2022influential citation
• Autologous exosome facilitates load and target delivery of bioactive peptides to repair spinal cord injury.

  2022cites this paper
• The potential of gene therapies for spinal cord injury repair: a systematic review and meta-analysis of pre-clinical studies

  2022cites this paper
• GDNF‐Loaded Polydopamine Nanoparticles‐Based Anisotropic Scaffolds Promote Spinal Cord Repair by Modulating Inhibitory Microenvironment

  2022cites this paper
• Peripherally delivered Adeno-associated viral vectors for spinal cord injury repair.

  2021cites this paper
• Neurotrophin-3 Promotes the Neuronal Differentiation of BMSCs and Improves Cognitive Function in a Rat Model of Alzheimer's Disease

  2021cites this paper
• An Adeno-Associated Viral vector encoding Neurotrophin 3 injected into affected forelimb muscles modestly improves sensorimotor function after contusive mid-cervical spinal cord injury

  2021cites this paper
• Retrograde Axonal Transport Property of Adeno-Associated Virus and Its Possible Application in Future.

  2021cites this paper
• Elucidating the Pivotal Neuroimmunomodulation of Stem Cells in Spinal Cord Injury Repair

  2021cites this paper
• Attenuation of Activated eIF2α Signaling by ISRIB Treatment After Spinal Cord Injury Improves Locomotor Function

  2021cites this paper
• Voluntary exercise ameliorates neuropathic pain by suppressing calcitonin gene-related peptide and ionized calcium-binding adapter molecule 1 overexpression in the lumbar dorsal horns in response to injury to the cervical spinal cord.

  2021cites this paper
• A Brief Summary of Current Therapeutic Strategies for Spinal Cord Injury

  2021cites this paper
• Exploring propriospinal neuron-mediated neural circuit plasticity using recombinant viruses after spinal cord injury.

  2021cites this paper
• Combinatory transplantation of mesenchymal stem cells with flavonoid small molecule in acellular nerve graft promotes sciatic nerve regeneration

  2020cites this paper
• Self-directed rehabilitation training intensity thresholds for efficient recovery of skilled forelimb function in rats with cervical spinal cord injury.

  2020cites this paper
• Feruloylated Oligosaccharides Alleviate Central Nervous Inflammation in Mice Following Spinal Cord Contusion.

  2020cites this paper
• Signatures of altered DNA methylation gene expression after central and peripheral nerve injury

  2020cites this paper
• The Translesional Spinal Network and Its Reorganization after Spinal Cord Injury

  2020cites this paper
• Early motor deficits in the phalangeal fine movements induced by chronic AMPA infusion in the rat spinal cord assessed by a novel method: Phalangeal tension recording test.

  2020cites this paper
• Epidural Electrical Stimulation: A Review of Plasticity Mechanisms That Are Hypothesized to Underlie Enhanced Recovery From Spinal Cord Injury With Stimulation

  2020cites this paper
• Inhibition of Brd4 by JQ1 Promotes Functional Recovery From Spinal Cord Injury by Activating Autophagy

  2020cites this paper
• Neurotrophin-3-mediated locomotor recovery: a novel therapeutic strategy targeting lumbar neural circuitry after spinal cord injury

  2020cites this paper
• The Influence of Neuron-Extrinsic Factors and Aging on Injury Progression and Axonal Repair in the Central Nervous System

  2020cites this paper
• Restoring Cellular Energetics Promotes Axonal Regeneration and Functional Recovery after Spinal Cord Injury.

  2020cites this paper
• Elevating sestrin2 attenuates endoplasmic reticulum stress and improves functional recovery through autophagy activation after spinal cord injury

  2020cites this paper
• Delayed peripheral treatment with neurotrophin-3 improves sensorimotor recovery after central nervous system injury

  2019cites this paper
• Descending motor circuitry required for NT-3 mediated locomotor recovery after spinal cord injury in mice

  2019cites this paper
• Histone deacetylase 6 inhibition restores autophagic flux to promote functional recovery after spinal cord injury.

  2019cites this paper
• Propriospinal Neurons: Essential Elements of Locomotor Control in the Intact and Possibly the Injured Spinal Cord

  2019cites this paper
• Shaw and Shal voltage‐gated potassium channels mediate circadian changes in Drosophila clock neuron excitability

  2019cites this paper
• Emerging molecular therapeutic targets for spinal cord injury

  2019cites this paper
• Initial researches on neuro-functional status and evolution in chronic ethanol consumers with recent traumatic spinal cord injury

  2019cites this paper
• Regeneration of Spinal Cord Connectivity Through Stem Cell Transplantation and Biomaterial Scaffolds

  2019cites this paper