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Title: Structural and functional locomotor network recovery in the transected spinal cord of Xenopus laevis tadpoles
Author: Anagianni, Sofia
ISNI:       0000 0004 7969 2002
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2019
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Spinal cord injury (SCI) in humans is detrimental and leads to varying degrees of sensory and motor impairments beyond the injury site due to the limited capacity of neuronal axons to regenerate and reconnect to their appropriate targets. In contrast, Xenopus laevis tadpoles demonstrate tremendous regenerative capabilities and achieve an almost complete recovery of locomotor function (swimming) after a spinal cord transection. Xenopus swimming activity is one of the rhythmic locomotor movements controlled by networks of spinal neurons termed as central pattern generators (CPGs). Locomotor CPGs range from simple networks with only a few neuronal members to highly complicated structures. However, little is known about how the CPG networks respond to injury. This thesis aims to investigate the recovery of the Xenopus swim CPG network following spinal transection by focusing on the extent of axonal regeneration through the lesion site and how this translates to functional recovery at the cellular and behavioural level. Xenopus tadpoles are excellent animal models for studying the repair of the spinal locomotor CPG network as it is much simpler than the mammalian system and has been extensively studied using in vivo preparations. The Xenopus embryonic CPG, at stage 37/38, is comprised of only four bilaterally represented neuronal types, excitatory descending interneurons (dIN), inhibitory ascending (aIN) and commissural (cIN) interneurons and motoneurons (mn). At this stage, tadpoles are already able to generate a rhythmic swimming behaviour. Following complete spinalisation, the tadpoles exhibited robust regeneration with both ascending and descending axons crossing the lesion site just one day later. Neuron proliferation was also increased and new-born neurons populated the area of the injury. Recovering tadpoles regained their swimming ability, however they did not reach control levels at one day post lesion since they displayed shorter swimming distance and lower speed. The tail bending frequency and angle of curvature were similar to the control siblings, but the tail displacement angle from the midline was smaller. In order to further explore the functional recovery of the spinal CPG network following SCI, simultaneous recordings of the motor nerve activity (ventral root) together with whole-cell current clamp recordings of single CPG neuron firing were performed on immobilised tadpoles. Results showed that recovering tadpoles can produce ventral root activity below the lesion site with the same properties in burst frequency and episode duration as the control siblings. Individual CPG neurons also exhibited similar electrical and firing properties to their control counterparts. As dopamine plays an important role in spinal locomotor control, including the swim CPG of Xenopus tadpoles, the response of CPG neurons to the putative D2 dopamine receptor agonist Quinpirole was tested and no significant difference was found. A surprising observation was that in some cases CPG neurons recorded rostral to the lesion site would fire inconsistently compared to the ventral root activity recorded below the lesion, a phenomenon which had never been observed before in control preparations. Simultaneous ventral root recordings from both sides of the lesion area confirmed that some recovering tadpoles exhibited different timing and duration of ventral root activity between the two sides. Further staining of single CPG neurons following patch recording revealed that not all axons crossed the injury site and those that extended beyond the lesion did not reach long distances indicating that a complete full-length axon regeneration might not be required for functional recovery. In conclusion, neuroregeneration following SCI is imperfect even in a permissive environment and a developing spinal cord, however functional recovery seems to not require a complete circuit reconstruction. Understanding the basic mechanisms of motor network recovery after injury in this simple vertebrate may reveal common mechanisms that can facilitate further research in mammalian systems and ultimately aid SCI rehabilitation and treatment in humans.
Supervisor: Zhang, Hongyan ; Becker, Catherina Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: spinal cord injury ; Xenopus laevis ; central pattern generators ; CPGs ; swim CPG networks ; regenerative capabilities ; neuroregeneration