Exploring the complete neurogenic potential of the brain – NeuroReserve

Programmed Cell Death (PCD) is strictly regulated during normal nervous system development to establish appropriate neural architecture, by allowing the generation of the correct numbers and diversity of neurons and glia, from insects to humans. Its dysregulation is associated with neurological diseases and brain cancers. One of its most recognized roles is the elimination of neurons that do not receive trophic support. However, the role of PCD in eliminating postmitotic neurons during specification is less characterized, although this role is of the utmost importance, since the diversity of neurons generated by a given species during development reflects its behavioural capacity. We posit that the ensemble of live and eliminated neurons is the entire set (reserve) of neurons, from which evolution chooses when facing environmental changes and requires to adapt. This proposal will test this hypothesis by 1) identifying the entire set of neurons that the fly brain can generate upon PCD inhibition and whether the surviving neurons (“undead” neurons) are already present as extant diversity in other insect species, 2) test whether “undead” neurons incorporate into functional circuits when forced to survive and 3) explore the behavioural space that these neurons may support. To achieve these goals, we will use the powerful Drosophila genetic toolkit to allow these neurons to survive, and will use single-cell RNA sequencing to identify and annotate them. This dataset will allow us to label these neurons and use trans-synaptic tracing tools to identify the circuits that they incorporate into in the adult. Finally, we will perform behavioural experiments to determine how visual behaviours are affected by the presence of otherwise eliminated neurons. This proposal will assess for the first time the complete neurogenic potential of the brain with single-cell resolution and the role of “undead” neurons as an evolutionary reserve for new circuits and behaviours.