Neurites Fishing for Energy: The Role of Mitochondrial Dynamics in Axonal Regeneration

Brain injury and neurodegenerative disorders represent a growing socio-economic problem in our aging society, partly because the central nervous system (CNS) of mammals has a limited regenerative capacity. Most of the injured neurons die, and the few survivors fail to extend their axons beyond the damaged site. Despite many years of research, functional circuit regeneration is still not possible. Strikingly, up till now, dendrites and their contribution to neuronal regeneration have been largely overlooked. Nevertheless, previous investigations in the host lab suggested that dendrite remodeling is required for spontaneous regrowth of axons in the adult zebrafish CNS. This PhD project aims, using a combination of innovative approaches, to confirm this refreshing theory at single-neuron level and validate the hypothesis that a reprogramming and relocation of the neuronal energy production machinery is needed for functional circuit restoration. Thereto, sparselylabeled transgenic zebrafish lines will be generated to study mitochondrial and metabolic processes at single-neuron level. Furthermore, potential target molecules involved in mitochondrial dynamics and bioenergetics underlying the different axonal/dendritic regrowth phases will be identified via a single-cell transcriptomic analysis. Subsequent validation of defined molecules/pathways should generate pivotal insights into how redirecting intra-neuronal energy channeling may promote neuronal repair in the mammalian CNS.