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Article
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Dual electrical stimulation at spinal-muscular interface reconstructs spinal sensorimotor circuits after spinal cord injury
Electrical signals with characteristic parameters for reconstructing neural circuits remain incompletely understood, limiting the therapeutic potential of electrical neuromodulation techniques. Here, the authors demonstrate that dual electrical stimulation at 10–20 Hz rebuilds the spinal sensorimotor neural circuit after spinal cord injury, indicating the characteristic signals of circuit remodeling.
- Kai Zhou
- , Wei Wei
- & Yaobo Liu
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Article
| Open Access
Fully implanted battery-free high power platform for chronic spinal and muscular functional electrical stimulation
Electrical stimulation of the neuromuscular system holds promise for therapeutic biomedical applications, but is currently restricted by power. Here, the authors introduce fully implantable resonator-based designs achieving ±20 V compliance and >300 mW output, enabling multichannel, biphasic, current-controlled operation to evoke functional gate patterns for 6-weeks in freely behaving rats.
- Alex Burton
- , Zhong Wang
- & Philipp Gutruf
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Article
| Open Access
Small leucine-rich proteoglycans inhibit CNS regeneration by modifying the structural and mechanical properties of the lesion environment
The mechanical properties of central nervous system (CNS) scar tissue are considered to contribute to axon regeneration failure. Here, the authors identify members of the small leucine-rich proteoglycan family as modulators of the inhibitory viscoelastic response of CNS lesions.
- Julia Kolb
- , Vasiliki Tsata
- & Daniel Wehner
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Article
| Open Access
Spinal cord repair is modulated by the neurogenic factor Hb-egf under direction of a regeneration-associated enhancer
Zebrafish can regenerate after paralyzing spine injuries and regain locomotor ability, unlike mammals. Here authors show that the neurogenic factor Hb-egf promotes spinal cord regeneration in zebrafish and is regulated by an enhancer that can similarly direct expression in the pro-regenerative setting of neonatal mice.
- Valentina Cigliola
- , Adam Shoffner
- & Kenneth D. Poss
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Article
| Open Access
Single-cell analysis reveals region-heterogeneous responses in rhesus monkey spinal cord with complete injury
The cellular responses below the lesion remain unclear after spinal cord injury (SCI). Here, authors show region-heterogeneous responses in the SCI monkey by single-cell transcriptomics analysis and uncover the mechanism of scaffold-based SCI repair.
- Yongheng Fan
- , Xianming Wu
- & Jianwu Dai
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Article
| Open Access
Porous microneedle patch with sustained delivery of extracellular vesicles mitigates severe spinal cord injury
Efficient delivery of extracellular vesicles to the injured spinal cord, with minimal damage, remains challenging. Here, the authors fabricate a minimally invasive microneedle device, which provides efficient and sustained extracellular vesicle delivery for spinal cord injury treatment.
- Ao Fang
- , Yifan Wang
- & Xuhua Wang
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Article
| Open Access
Androgens show sex-dependent differences in myelination in immune and non-immune murine models of CNS demyelination
Androgen effects have been poorly studied in demyelinating diseases in females. Here, authors show androgen requirement for proper myelin regeneration in females and the critical need to consider male-female differences in multiple sclerosis patients.
- Amina Zahaf
- , Abdelmoumen Kassoussi
- & Elisabeth Traiffort
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Article
| Open Access
Segmental motor recovery after cervical spinal cord injury relates to density and integrity of corticospinal tract projections
How the segmental innervation of upper limb muscles recovers after spinal cord injury is not fully understood. Here the authors show associations between corticospinal tract sparing and upper extremity recovery in spinal cord injury.
- Gustavo Balbinot
- , Guijin Li
- & Jose Zariffa
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Article
| Open Access
The alarmin interleukin-1α triggers secondary degeneration through reactive astrocytes and endothelium after spinal cord injury
The neuroimmune interactions driving secondary degeneration in the injured spinal cord remain elusive. Here, the authors reveal that damaged microglia release IL-1α, resulting in neutrophil infiltration and the loss of mature oligodendrocytes through astrocytic and endothelial IL-1R1 in mice.
- Floriane Bretheau
- , Adrian Castellanos-Molina
- & Steve Lacroix
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Article
| Open Access
Single cell atlas of spinal cord injury in mice reveals a pro-regenerative signature in spinocerebellar neurons
Matson et al. performed single nucleus sequencing of the “spared” spinal cord tissue distal to an injury in mice. They found that spinocerebellar neurons expressed a pro-regenerative gene signature and showed axon outgrowth after injury.
- Kaya J. E. Matson
- , Daniel E. Russ
- & Ariel J. Levine
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Article
| Open Access
Effects of biological sex mismatch on neural progenitor cell transplantation for spinal cord injury in mice
In this study, Pitonak et al. report that transplantation of neural progenitor cells derived from male donors trigger an immune rejection response following transplantation into sites of spinal cord injury in female mice.
- Michael Pitonak
- , Miriam Aceves
- & Jennifer N. Dulin
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Article
| Open Access
Microengineered devices enable long-term imaging of the ventral nerve cord in behaving adult Drosophila
Minimally invasive procedures for tracking neural activity are important for understanding of neural networks. Here the authors describe microfabricated implants and windows that enable long-term recordings of motor circuit activity in Drosophila, allowing them to watch how neurons change their structure and activity over weeks.
- Laura Hermans
- , Murat Kaynak
- & Pavan Ramdya
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Article
| Open Access
Transcription factor network analysis identifies REST/NRSF as an intrinsic regulator of CNS regeneration in mice
Here the authors couple an integrative genomic analysis with substantial in vitro and in vivo experimental validation, identifying REST as a novel suppressor of a pro-regenerative gene program and CNS axon regeneration in mice.
- Yuyan Cheng
- , Yuqin Yin
- & Daniel H. Geschwind
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Article
| Open Access
Chondroitin sulfate proteoglycans prevent immune cell phenotypic conversion and inflammation resolution via TLR4 in rodent models of spinal cord injury
Inflammation resolution failure is a pathological hallmark of spinal cord injury. Here, the authors show in rodents that chondroitin sulfate proteoglycans contribute to failed resolution by preventing immune cells at the injury core from converting to a pro-resolution phenotype, and this is mediated by TLR4.
- Isaac Francos-Quijorna
- , Marina Sánchez-Petidier
- & Elizabeth J. Bradbury
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Article
| Open Access
Spinal cord injury impairs cardiac function due to impaired bulbospinal sympathetic control
By combining experimental models with prospective clinical studies, the authors show that spinal cord injury causes a rapid reduction in cardiac function that precedes structural changes, and that the loss of descending sympathetic control is the major cause of reduced cardiac function following spinal cord injury.
- Mary P. M. Fossey
- , Shane J. T. Balthazaar
- & Christopher R. West
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Article
| Open Access
An injury-induced serotonergic neuron subpopulation contributes to axon regrowth and function restoration after spinal cord injury in zebrafish
The mechanisms involved in regeneration of the spinal cord after injury are unclear. Here, the authors show that a subpopulation of intraspinal serotonergic neurons localized at the injury site stimulates axonal regrowth of interneurons via 5-HT1B receptor, resulting in recovery of function following SCI in zebrafish.
- Chun-Xiao Huang
- , Yacong Zhao
- & Jianren Song
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Article
| Open Access
Confronting false discoveries in single-cell differential expression
Differential expression analysis of single-cell transcriptomics allows scientists to dissect cell-type-specific responses to biological perturbations. Here, the authors show that many commonly used methods are biased and can produce false discoveries.
- Jordan W. Squair
- , Matthieu Gautier
- & Grégoire Courtine
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Article
| Open Access
Pericyte-derived fibrotic scarring is conserved across diverse central nervous system lesions
Fibrotic scar tissue limits central nervous system regeneration. Here, Dias et al. show that fibrotic scarring is common in mice and humans, following distinct lesions to the adult brain and spinal cord, and derives from a discrete population of GLAST-expressing perivascular cells.
- David O. Dias
- , Jannis Kalkitsas
- & Christian Göritz
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Article
| Open Access
Locomotion dependent neuron-glia interactions control neurogenesis and regeneration in the adult zebrafish spinal cord
The mechanisms stimulating adult neurogenesis are unclear. Here, the authors show the contribution of cholinergic and GABAergic signalling within the locomotor network to spinal cord neurogenesis during homeostasis and regeneration, showing neurogenesis depends on circuit activity in the adult zebrafish.
- Weipang Chang
- , Andrea Pedroni
- & Konstantinos Ampatzis
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| Open Access
Co-occupancy identifies transcription factor co-operation for axon growth
After injury to the nervous system, many neurons fail to initiate transcriptional programs needed for axon growth. Here the authors examine co-operative binding of factors to regulatory DNA to predict combinations that improve axon growth when ectopically co-expressed.
- Ishwariya Venkatesh
- , Vatsal Mehra
- & Murray G. Blackmore
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Article
| Open Access
Multi-pronged neuromodulation intervention engages the residual motor circuitry to facilitate walking in a rat model of spinal cord injury
Deep brain stimulation and epidural electrical stimulation of the spinal cord enable locomotion in humans with spinal cord injury (SCI) but the potential synergy between both approaches is unclear. The authors show that a complex technological approach is required to enable volitional walking in rats with SCI.
- Marco Bonizzato
- , Nicholas D. James
- & Gregoire Courtine
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Article
| Open Access
Transneuronal delivery of hyper-interleukin-6 enables functional recovery after severe spinal cord injury in mice
The CNS has limited ability to regenerate following injury, Here, the authors show that a single injection of AAV-hyper-interleukin-6 in the sensory motor cortex results in corticospinal and raphe spinal tracts regeneration in the injured spinal cord as well as functional recovery in mice.
- Marco Leibinger
- , Charlotte Zeitler
- & Dietmar Fischer
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Article
| Open Access
Enriched conditioning expands the regenerative ability of sensory neurons after spinal cord injury via neuronal intrinsic redox signaling
Pre conditioning injury or environmental enrichment have been shown to promote axon regeneration. Here the authors show that environmental enrichment, combined with preconditioning injury promotes regeneration via a redox signalling dependent mechanism.
- Francesco De Virgiliis
- , Thomas H. Hutson
- & Simone Di Giovanni
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Article
| Open Access
Microenvironment-responsive immunoregulatory electrospun fibers for promoting nerve function recovery
Inflammatory responses determine the pathological course of spinal cord injury. Here, the authors report on pH responsive fibers for triggered release of IL-4 plasmid liposomes and sustained release of nerve growth factor to regulate the immune response and promote nerve regeneration to enhance functional recovery.
- Kun Xi
- , Yong Gu
- & Liang Chen
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Article
| Open Access
Spinal cord injury causes chronic bone marrow failure
Spinal cord injury (SCI) often leads to immune dysfunction, but mechanistic insights are still lacking. Here the authors show that SCI alters chemokine signaling and induces long, persisting defects in hematopoietic stem and progenitor cell migration, thereby entrapping them in the bone marrow and disrupting peripheral immune homeostasis.
- Randall S. Carpenter
- , Jessica M. Marbourg
- & Phillip G. Popovich
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Article
| Open Access
Rapid and robust restoration of breathing long after spinal cord injury
Respiratory failure is one of the leading causes of death following spinal cord injury and it is unclear if normal respiratory motor activity can be recovered after chronic injury-induced paralysis. Here, authors show that treatment with chondroitinase ABC induces robust rescue of breathing up to 1.5 years following complete hemidiaphragm paralysis.
- Philippa M. Warren
- , Stephanie C. Steiger
- & Jerry Silver
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Article
| Open Access
Locomotor recovery following contusive spinal cord injury does not require oligodendrocyte remyelination
The contribution of oligodendrocytes to remyelination in functional recovery after spinal cord injury is not fully understood. Here, the authors show that oligodendrocyte progenitor cell differentiation is not required for functional recovery after spinal cord injury in mice.
- Greg J. Duncan
- , Sohrab B. Manesh
- & Wolfram Tetzlaff
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Article
| Open Access
Injured adult motor and sensory axons regenerate into appropriate organotypic domains of neural progenitor grafts
Understanding how transplanted cells interact with the host nervous system will be important for cell based neural regeneration approaches. Here, the authors study the sensory fate of neural progenitor cell grafts transplanted to the injured spinal cord, and show that host axons retain the ability to distinguish appropriate and inappropriate graft targets.
- Jennifer N. Dulin
- , Andrew F. Adler
- & Mark H. Tuszynski
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Article
| Open Access
An injectable hydrogel enhances tissue repair after spinal cord injury by promoting extracellular matrix remodeling
The cystic cavity that develops following injuries to brain or spinal cord is a major obstacle. Here the authors show an injection of imidazole poly(organophosphazenes), a hydrogel with thermosensitive sol–gel transition behavior, almost completely eliminates cystic cavities in a clinically relevant rat spinal cord injury model.
- Le Thi Anh Hong
- , Young-Min Kim
- & Byung Gon Kim
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Article
| Open Access
Topological data analysis for discovery in preclinical spinal cord injury and traumatic brain injury
Data-driven discovery in complex neurological disorders has potential to extract meaningful knowledge from large, heterogeneous datasets. Here the authors apply topological data analysis to assess therapeutic effects in preclinical traumatic brain injury and spinal cord injury research studies.
- Jessica L. Nielson
- , Jesse Paquette
- & Adam R. Ferguson
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Large-scale reorganization of the somatosensory cortex following spinal cord injuries is due to brainstem plasticity
The reorganization of the mammalian somatosensory cortex is a common consequence of sensory deafferentation. Here, Kambi et al.show that reorganization of the cuneate nucleus in the brainstem is essential for the large-scale reorganization of the somatosensory cortex following sensory deafferentation in monkeys.
- Niranjan Kambi
- , Priyabrata Halder
- & Neeraj Jain
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In vivo conversion of astrocytes to neurons in the injured adult spinal cord
Expression of the transcription factor SOX2 reprogrammes astrocytes into neuroblasts in the adult mouse striatum. Here, the authors use the same approach in the injured adult mouse spinal cord to convert resident astrocytes into neuroblasts that can mature into synapse-forming neurons.
- Zhida Su
- , Wenze Niu
- & Chun-Li Zhang
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Article
| Open Access
Chondroitin sulphate N-acetylgalactosaminyl-transferase-1 inhibits recovery from neural injury
The glycosaminoglycan chondroitin sulphate inhibits axon growth. Here the authors show that mice deficient in chondroitin sulphate biosynthesis have increased levels of heparan sulphate, which is more efficient than chondroitinase in supporting recovery from spinal cord injury.
- Kosei Takeuchi
- , Nozomu Yoshioka
- & Michihiro Igarashi
Intrathecal delivery of adipose-derived mesenchymal stem cells in traumatic spinal cord injury: Phase I trial