Intraneuronal shift in bioenergetics as key for neuronal repair in the central nervous system

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. Up till now, the contribution of dendrites to CNS regeneration has been largely overlooked. Nevertheless, previous investigations in our lab suggested that dendrite remodeling and intraneuronal redistribution of mitochondria drives spontaneous axonal regrowth and functional recovery in the adult zebrafish CNS. Using a combination of innovative molecular, cellular and imaging approaches in zebrafish and mice, we aim to validate the refreshing hypothesis that a reprogramming and relocation of the neuronal energy production machinery is needed for functional recovery. Thereto, we will create pioneering microfluidic devices that enable to study mitochondrial and metabolic processes at single-neuron and compartment-specific level. Furthermore, potential target molecules involved in bioenergetics and underlying the different axonal/dendritic regrowth phases will be identified via single-cell transcriptomic analyses. Subsequent validation of defined molecules/pathways will generate pivotal insights into how intraneuronal energy channeling promotes neuronal repair in the mammalian CNS.