Focal neuronal loss and cell replacement in a connectome model of fly steering

Abstract

Focal neuronal loss after stroke, traumatic brain injury or spinal cord injury can disrupt circuits and result in persistent motor deficits. Which cells and connections must be restored to recover a specific behavior is difficult to establish experimentally. Here we use a connectome-constrained spiking model of the fruit-fly nervous system and decode motor-neuron output to simulate visually guided steering. After loss of 4,000 neurons, path straightness ranged from 0.04 to 0.95 depending on lesion location. At a fixed sensorimotor site, a 2,000-neuron lesion reduced simulated displacement to 6.5% of intact. Across 100 stochastic simulation realizations of the connectome, replacing 100 cells with their original connections increased displacement to 62.5% of intact when motor-control pathways were prioritized, compared with 10.1% after random selection of 100 cells and 48.5% after random selection of 1,000 cells. When connections were instead inferred from cell type, the same 100 intended replacements reached 60.0% of intact with matched identities and 6.7% with non-target identities, indicating that cell identity and type-dependent integration are required for recovery. Our model generates testable predictions for genetic ablation experiments in fruit flies and identifies candidate cellular and circuit requirements for motor repair that can inform cell replacement therapies and future models of mammalian locomotion.