Regeneration and neural circuits in the spinal cord : an imaging study on zebrafish

The reversal of spinal cord injury (SCI) and its devastating effect on voluntary control is one of the most provocative challenges in neuroscience research. Preclinical and clinical research has for a very long time tried to address this challenge, but there is still no effective treatment that leads to functional recovery. In simplified terms, the spinal cord resembles a highway, with outgoing commands from the brain and incoming feedback from the periphery. However, the spinal cord is an extremely complex apparatus with billions of cells, connections, and neuronal circuits. Injury to the spinal cord in humans has acute disastrous effects, followed by secondary pathophysiological events leading to a permanent loss of sensation and motor function corresponding to the site of injury. The spinal cord of humans, as far as we know, lacks the capacity to regenerate after an injury, in contrast to that of vertebrate fish, such as the zebrafish, which has an extraordinary ability to regenerate. Investigating the regenerative capacity of zebrafish can unveil mechanisms and features that may be translatable to the clinic.

In paper I, we identified V2a interneurons as an intrinsic source of excitation and a necessity for the zebrafish larvae’s normal generation of locomotor rhythm. In paper II, we scaled up and developed the technique used in paper I to a robust method to induce precise spatial and temporal SCI with minimal collateral damage in zebrafish larvae. In paper III, we investigated the impact of several factors, including lesion size, hypothermia, and analgesic substances, on the functional recovery of zebrafish larvae following SCI. Furthermore, we examined intrinsic Ca2+ signaling before and after SCI. In summary, this thesis paves the way for further investigations of the remarkable regenerative capacity zebrafish possess.

List of scientific papers

I. Eklöf-Ljunggren E, Haupt S, Ausborn J, Dehnisch I, Uhlén P, Higashijima S, El Manira A. Origin of excitation underlying locomotion in the spinal circuit of zebrafish. Proceedings of the National Academy of Sciences U S A. 2012 Apr 3;109(14):5511-16.
https://doi.org/10.1073/pnas.1115377109

II. Dehnisch Ellström I, Spulber S, Hultin S, Norlin N, Ceccatelli S, Hultling C, Uhlén P. Spinal cord injury in zebrafish induced by near-infrared femtosecond laser pulses. Journal of Neuroscience Methods. 2019; 31: 259-266.
https://doi.org/10.1016/j.jneumeth.2018.10.035

III. Dehnisch Ellström I, Louhivouri L, Norlin N, Hultling C, Uhlén P. Impact of lesion size, hypothermia, and analgesics on locomotor recovery in spinal cord injured zebrafish. [Manuscript]