Chemotropic guidance facilitates axonal regeneration and synapse formation after spinal cord injury

Alto, Laura Taylor; Havton, Leif A.; Conner, J. M.; Hollis, Edmund R.; Blesch, Armin; Tuszynski, Mark H.

doi:10.1038/nn.2365

Cited by 196 publications

(180 citation statements)

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“…Graded expression of NT-3 has been used to induce chemotropic regeneration of ascending sensory axons [60,110]. In animals with low levels of NT-3 expression within a permissive dorsal column graft and higher levels in the spinal cord beyond the lesion, sensory axons are able to regenerate through the site of injury and reconstitute damaged neuronal circuitry (Fig.…”

Section: Neurotrophins and Spinal Cord Regenerationmentioning

confidence: 99%

“…In animals with low levels of NT-3 expression within a permissive dorsal column graft and higher levels in the spinal cord beyond the lesion, sensory axons are able to regenerate through the site of injury and reconstitute damaged neuronal circuitry (Fig. 1) [60,110]. Once sensory axons have re-entered host tissue, they can be guided to NT-3-secreting nuclei several millimeters away and form synapses on neurons in the appropriate target nucleus [110].…”

Section: Neurotrophins and Spinal Cord Regenerationmentioning

confidence: 99%

“…1) [60,110]. Once sensory axons have re-entered host tissue, they can be guided to NT-3-secreting nuclei several millimeters away and form synapses on neurons in the appropriate target nucleus [110]. These synapses in nucleus gracilis are indistinguishable from intact synapses at the ultrastructural level, containing clusters of synaptic vesicles.…”

Section: Neurotrophins and Spinal Cord Regenerationmentioning

confidence: 99%

“…These synapses in nucleus gracilis are indistinguishable from intact synapses at the ultrastructural level, containing clusters of synaptic vesicles. However, the newly formed regenerated projections are not electrophysiologically active, possibly due in part to a failure of remyelination [110].…”

Section: Neurotrophins and Spinal Cord Regenerationmentioning

confidence: 99%

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Neurotrophins: Potential Therapeutic Tools for the Treatment of Spinal Cord Injury

Hollis

Tuszynski

2011

Neurotherapeutics

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Spinal cord injury permanently disrupts neuroanatomical circuitry and can result in severe functional deficits. These functional deficits, however, are not immutable and spontaneous recovery occurs in some patients. It is highly likely that this recovery is dependent upon spared tissue and the endogenous plasticity of the central nervous system. Neurotrophic factors are mediators of neuronal plasticity throughout development and into adulthood, affecting proliferation of neuronal precursors, neuronal survival, axonal growth, dendritic arborization and synapse formation. Neurotrophic factors are therefore excellent candidates for enhancing axonal plasticity and regeneration after spinal cord injury. Understanding growth factor effects on axonal growth and utilizing them to alter the intrinsic limitations on regenerative growth will provide potent tools for the development of translational therapeutic interventions for spinal cord injury.Keywords Neurotrophin . spinal cord injury . regeneration . axon plasticity . functional recovery Human Spinal Cord InjuryTraumatic injury of the spinal cord can produce a range of debilitating effects and permanently alter the capabilities and quality of life of its surviving victims. Damage to the central nervous system (CNS) in general results in destruction of neuronal circuitry. Contusion, compression, and penetration injuries of the spinal cord can interrupt the flow of sensory and motor information between the brain and periphery [1]. Depending on the location and severity of the injury, deficits can range from weakness of limb movement to total paralysis and ventilator-assisted respiration. Spontaneous functional recovery is limited, but can and often does occur in patients with initial sparing of sensorimotor function [2]. This recovery, which plateaus between 12 to 18 months, is very likely due to sparing and sprouting of axons within the zone of partial preservation, an area where some motor function remains intact, immediately adjacent to the lesion site [2].Approximately 40% of humans that sustain spinal cord injury (SCI) exhibit improvement from their early postinjury baseline, and this spontaneous recovery can range from modest to extensive [2]. Spontaneous recovery primarily appears to depend on the extent of tissue sparing at the injury site, allowing compensatory axonal sprouting and systems reorganization at levels ranging from the spinal cord to the cerebral cortex [3][4][5][6][7][8][9][10]. However, in cases of more severe injuries, means of enhancing endogenous levels of axonal sprouting and inducing true axonal regeneration are required to enhance functional outcomes.Electronic supplementary material The online version of this article

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Section: Neurotrophins and Spinal Cord Regenerationmentioning

confidence: 99%

Section: Neurotrophins and Spinal Cord Regenerationmentioning

confidence: 99%

Section: Neurotrophins and Spinal Cord Regenerationmentioning

confidence: 99%

Section: Neurotrophins and Spinal Cord Regenerationmentioning

confidence: 99%

See 2 more Smart Citations

Neurotrophins: Potential Therapeutic Tools for the Treatment of Spinal Cord Injury

Hollis

Tuszynski

2011

Neurotherapeutics

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“…Does the pattern of any regrowth recapitulate developmental axon growth or does it employ a distinct growth programme? These questions are particularly important now that many experimental manipulations can successfully initiate axon regeneration in the adult injured CNS [5][6][7] . We hypothesized that axons that normally display a high rate of synaptic and branch remodelling, that is, from Layer (L) 6 cortical cells would more readily respond to a lesion than axons that are typically more stable, that is, thalamocortical axons (TCA) projecting to the upper layers of the cortex 8 .…”

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confidence: 99%

In-vivo single neuron axotomy triggers axon regeneration to restore synaptic density in specific cortical circuits

et al. 2013

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To what extent, how and when axons respond to injury in the highly interconnected grey matter is poorly understood. Here we use two-photon imaging and focused ion beamscanning electron microscopy to explore, at synaptic resolution, the regrowth capacity of several neuronal populations in the intact brain. Time-lapse analysis of 4100 individually ablated axons for periods of up to a year reveals a surprising inability to regenerate even in a glial scar-free environment. However, depending on cell type some axons spontaneously extend for distances unseen in the unlesioned adult cortex and at maximum speeds comparable to peripheral nerve regeneration. Regrowth follows a distinct pattern from developmental axon growth. Remarkably, although never reconnecting to the original targets, axons consistently form new boutons at comparable prelesion synaptic densities, implying the existence of intrinsic homeostatic programmes, which regulate synaptic numbers on regenerating axons. Our results may help guide future clinical investigations to promote functional axon regeneration.

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Neurotrophins and neural stem cells in posttraumatic brain injury repair

Guo,

Liu,

Wang

et al. 2023

Anim Models and Exp Med

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Traumatic brain injury (TBI) is the main cause of disability, mental health disorder, and even death, with its incidence and social costs rising steadily. Although different treatment strategies have been developed and tested to mitigate neurological decline, a definitive cure for these conditions remains elusive. Studies have revealed that various neurotrophins represented by the brain‐derived neurotrophic factor are the key regulators of neuroinflammation, apoptosis, blood–brain barrier permeability, neurite regeneration, and memory function. These factors are instrumental in alleviating neuroinflammation and promoting neuroregeneration. In addition, neural stem cells (NSC) contribute to nerve repair through inherent neuroprotective and immunomodulatory properties, the release of neurotrophins, the activation of endogenous NSCs, and intercellular signaling. Notably, innovative research proposals are emerging to combine BDNF and NSCs, enabling them to synergistically complement and promote each other in facilitating injury repair and improving neuron differentiation after TBI. In this review, we summarize the mechanism of neurotrophins in promoting neurogenesis and restoring neural function after TBI, comprehensively explore the potential therapeutic effects of various neurotrophins in basic research on TBI, and investigate their interaction with NSCs. This endeavor aims to provide a valuable insight into the clinical treatment and transformation of neurotrophins in TBI, thereby promoting the progress of TBI therapeutics.

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Chemotropic guidance facilitates axonal regeneration and synapse formation after spinal cord injury

Cited by 196 publications

References 50 publications

Neurotrophins: Potential Therapeutic Tools for the Treatment of Spinal Cord Injury

Neurotrophins: Potential Therapeutic Tools for the Treatment of Spinal Cord Injury

In-vivo single neuron axotomy triggers axon regeneration to restore synaptic density in specific cortical circuits

Neurotrophins and neural stem cells in posttraumatic brain injury repair

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