Regulation of axonal regeneration following spinal cord injury in the lamprey

Following rostral spinal cord injury (SCI) in larval lampreys, injured descending brain neurons, particularly reticulospinal (RS) neurons, regenerate their axons, and locomotor behavior recovers in a few weeks. However, axonal regeneration of descending brain neurons is mostly limited to relatively short distances, but the mechanisms for incomplete axonal regeneration are unclear. First, lampreys with rostral SCI exhibited greater axonal regeneration of descending brain neurons, including RS neurons, as well as more rapid recovery of locomotor muscle activity right below the lesion site, compared with animals with caudal SCI. In addition, following rostral SCI, most injured RS neurons displayed the “injury phenotype,” whereas following caudal SCI, most injured neurons displayed normal electrical properties. Second, following rostral SCI, at cold temperatures (~4–5°C), axonal transport was suppressed, axonal regeneration and behavioral recovery were blocked, and injured RS neurons displayed normal electrical properties. Cold temperatures appear to prevent injured RS neurons from detecting and/or responding to SCI. It is hypothesized that following rostral SCI, injured descending brain neurons are strongly stimulated to regenerate their axons, presumably because of elimination of spinal synapses and reduced neurotrophic support. However, when these neurons regenerate their axons and make synapses right below the lesion site, restoration of neurotrophic support very likely suppress further axonal regeneration. In contrast, caudal SCI is a weak stimulus for axonal regeneration, presumably because of spared synapses above the lesion site. These results may have implications for mammalian SCI, which can spare synapses above the lesion site for supraspinal descending neurons and propriospinal neurons. NEW & NOTEWORTHY Lampreys with rostral spinal cord injury (SCI) exhibited greater axonal regeneration of descending brain neurons and more rapid recovery of locomotor muscle activity below the lesion site compared with animals with caudal SCI. In addition, following rostral SCI, most injured reticulospinal (RS) neurons displayed the “injury phenotype,” whereas following caudal SCI, most injured neurons had normal electrical properties. We hypothesize that following caudal SCI, the spared synapses of injured RS neurons might limit axonal regeneration and behavioral recovery.

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Changes in properties of lamprey reticulospinal neurons following spinal cord injury

10.32469/10355/50140 ◽

2015 ◽

Author(s):

◽

Timothee Pale

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Electrical Properties ◽

Neurite Outgrowth ◽

Axonal Transport ◽

Axonal Regeneration ◽

Retrograde Axonal Transport ◽

Slight Reduction ◽

Synaptic Inputs ◽

Cord Injury

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] The lamprey is one of the most ancient vertebrates, sharing many of basic characteristics of the brain and spinal cord with higher, more evolved vertebrates such as mammals. However, unlike humans and other higher vertebrates, lampreys display robust axonal regeneration in the central nervous system following spinal cord injury (SCI). For instance, axons of reticulospinal (RS) neurons in the brain can regenerate and reconnect with spinal targets leading to recovery of locomotor behavior within a few weeks following SCI. During axonal regeneration, at [about]2-3 weeks following SCI, injured RS neurons display dramatic changes in their electrical properties (i.e. "injury phenotype", absence of 2/3 afterpotentials) compared to uninjured neurons. These changes may be due to axonal injury itself, interruption of retrograde axonal transport, and/or changes in synaptic inputs. The present work will focus on several aspects of lamprey RS neurons following SCI. (1) Can activation of second messenger signaling pathways stimulate neurite outgrowth of lamprey RS neurons without altering their electrical properties? (2) Does axotomy affect Ca2+ and SK channels and their underlying conductances? (3) Are the changes in biophysical properties of RS neurons following SCI due, in part, to disruption of retrograde axonal transport? (4) Does SCI lead to changes in morphology and synaptic inputs of injured lamprey RS neurons? For lamprey RS neurons in culture, activation of cAMP pathways stimulated neurite outgrowth. In brainspinal cord preparations, forskolin resulted in action potential broadening, at least for uninjured RS neurons, which would very likely increase calcium influx. In contrast, for lamprey RS neurons, dbcAMP stimulated neurite outgrowth without altering their electrical properties. These results suggest that activation of cAMP signaling may be an effective approach for stimulating axonal regeneration of RS neurons following spinal cord injury. Our results suggest that there may be little differences in Ca2+ currents and SK currents between injured and uninjured large RS neurons. Perhaps the slight reduction in the total Ca2+ influx combined with a slight reduction of SK current (fewer activated by Ca2+) is responsible for the abolishment of the sAHP in lamprey RS neurons [about]2-3 weeks following injury. In uninjured large RS neurons that were not physically damaged by the application of the microtubuledisrupting agent vinblastine, blocking retrograde axonal transport caused some neurons to fire erratically and display the "injury phenotype", which is typical for axotomized neurons following SCI. These results suggest that retrograde axonal transport may play an important role in the maintenance of normal electrical properties in uninjured lamprey large RS neurons. Additionally, these results suggest that following SCI, interruption of retrograde axonal transport perhaps contributes to the changes in electrical properties (i.e "injury phenotype") in injured lamprey RS neurons. Injured large RS neurons did not display significant differences in the amplitudes of their synaptic responses from stimulation of the oral hood compared to uninjured neurons whether they were stimulated contralaterally or ipsilaterally, and synaptic responses of injured and uninjured RS neurons from stimulations on either the right or the left side of the oral hood were not significantly different. Taken together, these results suggest that injury does not substantially alter the synaptic inputs of injured large RS neurons. Following rostral SCI in lampreys, large injured RS neurons did not display significant changes in their basic morphology of lamprey large RS neurons. For example, the major and minor diameters of injured large RS neurons were not significantly different than those of uninjured neurons. In addition, compared to uninjured neurons, injured neurons did not have different number of primary and secondary dendrites. These results suggest that SCI does not substantially alter the basic morphology of large lamprey RS neurons. The present work provided a better understanding of the mechanisms underlying the biophysical changes of injured lamprey RS neurons during axonal regeneration. These findings could help in the development of novel therapeutic strategies to enhance axonal regeneration, following spinal cord injury in higher vertebrates, including perhaps humans.

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Spinal Cord Injury: Lessons from Locomotor Recovery and Axonal Regeneration in Lower Vertebrates

The Neuroscientist ◽

10.1177/107385849800400414 ◽

1998 ◽

Vol 4 (4) ◽

pp. 250-263 ◽

Cited By ~ 23

Author(s):

Andrew D. McClellan

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Neural Development ◽

Axonal Regeneration ◽

Spinal Cord Injuries ◽

Axonal Guidance ◽

Behavioral Recovery ◽

Locomotor Function ◽

Cord Injury ◽

Lower Vertebrates

After severe spinal cord injury in adult higher vertebrates (birds and mammals), there normally is little or no axonal regeneration and virtually no recovery of voluntary locomotor function below the lesion. In contrast, certain lower vertebrates, including lamprey, fish, and some amphibians, exhibit robust axonal regeneration and substantial recovery of locomotor function after spinal cord injury. The remarkable behavioral recovery of lower vertebrates with spinal cord injuries is due to at least three factors: 1) minimal hemorrhagic necrosis at the injury site and the lack of a neurite growth–inhibiting astrocytic scar, 2) an environment in the spinal cord that is permissive for axonal regeneration, and 3) mechanisms for directed axonal elongation and selection of appropriate postsynaptic targets. The latter two features probably represent developmental mechanisms for axonal guidance and synaptogenesis that persist in the nervous systems of these animals well beyond the main phase of neural development. In the injured spinal cords of higher vertebrates, the full complement of manipulations necessary to promote functional regeneration and behavioral recovery is unknown. An understanding of the mechanisms that result in repair of spinal cord injuries in lower vertebrates may provide guidelines for identifying the requirements for functional spinal cord regeneration in higher vertebrates, including humans.

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Faculty Opinions recommendation of Regeneration of dorsal column fibers into and beyond the lesion site following adult spinal cord injury.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1001592.11054 ◽

2001 ◽

Author(s):

Marie Filbin

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Dorsal Column ◽

Lesion Site ◽

Cord Injury ◽

Adult Spinal Cord

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Faculty Opinions recommendation of Delayed implantation of intramedullary chitosan channels containing nerve grafts promotes extensive axonal regeneration after spinal cord injury.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1120587.576798 ◽

2008 ◽

Author(s):

Robert Ruff

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Axonal Regeneration ◽

Nerve Grafts ◽

Delayed Implantation ◽

Cord Injury

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Faculty Opinions recommendation of Chemotropic guidance facilitates axonal regeneration and synapse formation after spinal cord injury.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1163340.674068 ◽

2009 ◽

Author(s):

Michael Fehlings

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Axonal Regeneration ◽

Synapse Formation ◽

Cord Injury

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

Nature Neuroscience ◽

10.1038/nn.2365 ◽

2009 ◽

Vol 12 (9) ◽

pp. 1106-1113 ◽

Cited By ~ 142

Author(s):

Laura Taylor Alto ◽

Leif A Havton ◽

James M Conner ◽

Edmund R Hollis II ◽

Armin Blesch ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Axonal Regeneration ◽

Synapse Formation ◽

Cord Injury

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Effects of Functional Electrical Stimulation Cycling of Different Duration on Viscoelastic and Electromyographic Properties of the Knee in Patients with Spinal Cord Injury

Brain Sciences ◽

10.3390/brainsci11010007 ◽

2020 ◽

Vol 11 (1) ◽

pp. 7

Author(s):

Antonino Casabona ◽

Maria Stella Valle ◽

Claudio Dominante ◽

Luca Laudani ◽

Maria Pia Onesta ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Electrical Stimulation ◽

Functional Electrical Stimulation ◽

Muscle Activity ◽

Response Times ◽

Electromyographic Activity ◽

Functional Changes ◽

Pendulum Test ◽

Cord Injury

The benefits of functional electrical stimulation during cycling (FES-cycling) have been ascertained following spinal cord injury. The instrumented pendulum test was applied to chronic paraplegic patients to investigate the effects of FES-cycling of different duration (20-min vs. 40-min) on biomechanical and electromyographic characterization of knee mobility. Seven adults with post-traumatic paraplegia attended two FES-cycling sessions, a 20-min and a 40-min one, in a random order. Knee angular excursion, stiffness and viscosity were measured using the pendulum test before and after each session. Surface electromyographic activity was recorded from the rectus femoris (RF) and biceps femoris (BF) muscles. FES-cycling led to reduced excursion (p < 0.001) and increased stiffness (p = 0.005) of the knee, which was more evident after the 20-min than 40-min session. Noteworthy, biomechanical changes were associated with an increase of muscle activity and changes in latency of muscle activity only for 20-min, with anticipated response times for RF (p < 0.001) and delayed responses for BF (p = 0.033). These results indicate that significant functional changes in knee mobility can be achieved by FES-cycling for 20 min, as evaluated by the pendulum test in patients with chronic paraplegia. The observed muscle behaviour suggests modulatory effects of exercise on spinal network aimed to partially restore automatic neuronal processes.

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Descending propriospinal neurons mediate restoration of locomotor function following spinal cord injury

Journal of Neurophysiology ◽

10.1152/jn.00544.2016 ◽

2017 ◽

Vol 117 (1) ◽

pp. 215-229 ◽

Cited By ~ 10

Author(s):

Katelyn N. Benthall ◽

Ryan A. Hough ◽

Andrew D. McClellan

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Axonal Regeneration ◽

Central Pattern Generators ◽

Burst Activity ◽

Compensatory Mechanism ◽

Spinal Lesions ◽

Cord Injury ◽

Recovery Times ◽

Indirect Activation

Following spinal cord injury (SCI) in the lamprey, there is virtually complete recovery of locomotion within a few weeks, but interestingly, axonal regeneration of reticulospinal (RS) neurons is mostly limited to short distances caudal to the injury site. To explain this situation, we hypothesize that descending propriospinal (PS) neurons relay descending drive from RS neurons to indirectly activate spinal central pattern generators (CPGs). In the present study, the contributions of PS neurons to locomotor recovery were tested in the lamprey following SCI. First, long RS neuron projections were interrupted by staggered spinal hemitransections on the right side at 10% body length (BL; normalized from the tip of the oral hood) and on the left side at 30% BL. For acute recovery conditions (≤1 wk) and before axonal regeneration, swimming muscle burst activity was relatively normal, but with some deficits in coordination. Second, lampreys received two spaced complete spinal transections, one at 10% BL and one at 30% BL, to interrupt long-axon RS neuron projections. At short recovery times (3–5 wk), RS and PS neurons will have regenerated their axons for short distances and potentially established a polysynaptic descending command pathway. At these short recovery times, swimming muscle burst activity had only minor coordination deficits. A computer model that incorporated either of the two spinal lesions could mimic many aspects of the experimental data. In conclusion, descending PS neurons are a viable mechanism for indirect activation of spinal locomotor CPGs, although there can be coordination deficits of locomotor activity. NEW & NOTEWORTHY In the lamprey following spinal lesion-mediated interruption of long axonal projections of reticulospinal (RS) neurons, sensory stimulation still elicited relatively normal locomotor muscle burst activity, but with some coordination deficits. Computer models incorporating the spinal lesions could mimic many aspects of the experimental results. Thus, after disruption of long-axon projections from RS neurons in the lamprey, descending propriospinal (PS) neurons appear to be a viable compensatory mechanism for indirect activation of spinal locomotor networks.

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