scholarly journals Dorsal Root Injury—A Model for Exploring Pathophysiology and Therapeutic Strategies in Spinal Cord Injury

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2185
Author(s):  
Håkan Aldskogius ◽  
Elena N. Kozlova
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Dorsal Root ◽  
Molecular Mechanisms ◽  
Dorsal Root Ganglion Neurons ◽  
Descending Pathways ◽  
In Vivo Models ◽  
Root Injury ◽  
Cord Injury ◽  
Ganglion Neurons

Unraveling the cellular and molecular mechanisms of spinal cord injury is fundamental for our possibility to develop successful therapeutic approaches. These approaches need to address the issues of the emergence of a non-permissive environment for axonal growth in the spinal cord, in combination with a failure of injured neurons to mount an effective regeneration program. Experimental in vivo models are of critical importance for exploring the potential clinical relevance of mechanistic findings and therapeutic innovations. However, the highly complex organization of the spinal cord, comprising multiple types of neurons, which form local neural networks, as well as short and long-ranging ascending or descending pathways, complicates detailed dissection of mechanistic processes, as well as identification/verification of therapeutic targets. Inducing different types of dorsal root injury at specific proximo-distal locations provide opportunities to distinguish key components underlying spinal cord regeneration failure. Crushing or cutting the dorsal root allows detailed analysis of the regeneration program of the sensory neurons, as well as of the glial response at the dorsal root-spinal cord interface without direct trauma to the spinal cord. At the same time, a lesion at this interface creates a localized injury of the spinal cord itself, but with an initial neuronal injury affecting only the axons of dorsal root ganglion neurons, and still a glial cell response closely resembling the one seen after direct spinal cord injury. In this review, we provide examples of previous research on dorsal root injury models and how these models can help future exploration of mechanisms and potential therapies for spinal cord injury repair.

scholarly journals Cbp-dependent histone acetylation mediates axon regeneration induced by environmental enrichment in rodent spinal cord injury models

2019 ◽  
Vol 11 (487) ◽  
pp. eaaw2064 ◽  
Author(s):  
Thomas H. Hutson ◽  
Claudia Kathe ◽  
Ilaria Palmisano ◽  
Kay Bartholdi ◽  
Arnau Hervera ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Histone Acetylation ◽  
Neuronal Activity ◽  
Neuronal Plasticity ◽  
Environmental Enrichment ◽  
Dorsal Root Ganglion Neurons ◽  
Motor Functions ◽  
Cord Injury ◽  
Ganglion Neurons

After a spinal cord injury, axons fail to regenerate in the adult mammalian central nervous system, leading to permanent deficits in sensory and motor functions. Increasing neuronal activity after an injury using electrical stimulation or rehabilitation can enhance neuronal plasticity and result in some degree of recovery; however, the underlying mechanisms remain poorly understood. We found that placing mice in an enriched environment before an injury enhanced the activity of proprioceptive dorsal root ganglion neurons, leading to a lasting increase in their regenerative potential. This effect was dependent on Creb-binding protein (Cbp)–mediated histone acetylation, which increased the expression of genes associated with the regenerative program. Intraperitoneal delivery of a small-molecule activator of Cbp at clinically relevant times promoted regeneration and sprouting of sensory and motor axons, as well as recovery of sensory and motor functions in both the mouse and rat model of spinal cord injury. Our findings showed that the increased regenerative capacity induced by enhancing neuronal activity is mediated by epigenetic reprogramming in rodent models of spinal cord injury. Understanding the mechanisms underlying activity-dependent neuronal plasticity led to the identification of potential molecular targets for improving recovery after spinal cord injury.

scholarly journals Profiling sensory neuron microenvironment after peripheral and central axon injury reveals key pathways for neural repair

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Oshri Avraham ◽  
Rui Feng ◽  
Eric Edward Ewan ◽  
Justin Rustenhoven ◽  
Guoyan Zhao ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Peripheral Nerve ◽  
Nerve Injury ◽  
Peripheral Nerve Injury ◽  
Dorsal Root ◽  
Axon Regeneration ◽  
Cell Type ◽  
Root Injury ◽  
Cord Injury

Sensory neurons with cell bodies in dorsal root ganglia (DRG) represent a useful model to study axon regeneration. Whereas regeneration and functional recovery occurs after peripheral nerve injury, spinal cord injury or dorsal root injury is not followed by regenerative outcomes. Regeneration of sensory axons in peripheral nerves is not entirely cell autonomous. Whether the DRG microenvironment influences the different regenerative capacities after injury to peripheral or central axons remains largely unknown. To answer this question, we performed a single-cell transcriptional profiling of mouse DRG in response to peripheral (sciatic nerve crush) and central axon injuries (dorsal root crush and spinal cord injury). Each cell type responded differently to the three types of injuries. All injuries increased the proportion of a cell type that shares features of both immune cells and glial cells. A distinct subset of satellite glial cells (SGC) appeared specifically in response to peripheral nerve injury. Activation of the PPARα signaling pathway in SGC, which promotes axon regeneration after peripheral nerve injury, failed to occur after central axon injuries. Treatment with the FDA-approved PPARα agonist fenofibrate increased axon regeneration after dorsal root injury. This study provides a map of the distinct DRG microenvironment responses to peripheral and central injuries at the single-cell level and highlights that manipulating non-neuronal cells could lead to avenues to promote functional recovery after CNS injuries or disease.

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

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jacob Matthews ◽  
Sarina Surey ◽  
Liam M. Grover ◽  
Ann Logan ◽  
Zubair Ahmed
Keyword(s):  
Drug Delivery ◽  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Dorsal Column ◽  
Dorsal Root Ganglion Neurons ◽  
Sensory Function ◽  
Adult Rats ◽  
Bovine Collagen ◽  
Cord Injury ◽  
Ganglion Neurons

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

Neurotrophin 3 Improves Delayed Reconstruction of Sensory Pathways After Cervical Dorsal Root Injury

Neurosurgery ◽  
2011 ◽  
Vol 68 (2) ◽  
pp. 450-461 ◽  
Author(s):  
Song Liu ◽  
Stephane Blanchard ◽  
Stephanie Bigou ◽  
Sandrine Vitry ◽  
Delphine Bohl ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Dorsal Root ◽  
Nerve Graft ◽  
Dorsal Root Ganglion Neurons ◽  
Adult Rats ◽  
Sensory Pathways ◽  
Sensory Axons ◽  
Neurotrophin 3 ◽  
Root Injury ◽  
Ganglion Neurons

Abstract BACKGROUND: Spinal root avulsion, or section, results in devastating functional sequels. Whereas reconstruction of motor pathways based on neurotization can reduce motor deficit, associated permanent limb anesthesia limits expected benefit. Sensory pathway reconstruction after dorsal root injury is limited by the inability of re-growing central sensory axons to enter the spinal cord through an injured root. OBJECTIVE: To provide evidence for the reconnection of C7 DRG neurons with the central nervous system (CNS) after experimental section of the C7 dorsal root in adult rats. METHODS: We assessed a new reconstruction strategy in adult rats 9 weeks after transection of C6 and C7 dorsal roots. Re-growing C7 central sensory axons were redirected to the noninjured C5 dorsal root through a nerve graft by end-to-side anastomosis that did not alter the C5 conduction properties. In a subgroup of rats, surgical reconstruction was combined with lentivirus-mediated gene transfer to the nerve graft in order to overexpress neurotrophin 3 (NT-3), a neurotrophic factor that stimulates sensory axon regeneration. RESULTS: Four months after reconstruction, recording of sensory evoked potentials and fluorescent tracer transport showed electrical and physical reconnection of the C7 dorsal root ganglion neurons to the spinal cord through the reconstructed pathway. Sensory perception recovery predominated on proprioception. Axonal regrowth and perception were improved when the nerve graft overexpressed neurotrophin-3 at the time of transplantation. Neurotrophin-3 overexpression did not persist 4 months after transplantation. CONCLUSION: Efficient and functional reconnection of dorsal root ganglion neurons to the spinal cord can be achieved in rats several weeks after cervical dorsal root injury. Surgical repair of sensory pathways could be considered in combination with motor nerve neurotization to treat persisting severe upper limb disability in humans.

Sign in / Sign up

Export Citation Format

Share Document