Fig. 8

Comparison between wild-type and nlrc3l mutant zebrafish conveys our current model. Sensory transduction based on a visuomotor response remains intact in nlrc3l mutants, while we show that immunomodulation is an important factor regulating larval zebrafish locomotion at steady state. The overall results suggest an inhibitory effect from macrophage-induced inflammation compounded by microglia loss on dopamine neurotransmission and subsequent activation of the descending neural circuits executing daytime locomotion. The neural circuits underlying locomotor drive may constitute diencephalic dopaminergic clusters (DDC) that either directly activate the spinal circuits (that include the central pattern generator (CPG)), or indirectly activate the mesencephalic locomotor region (MLR) and reticulospinal neurons (RS) to execute or potentiate swimming. Macrophage-induced inflammation activates neutrophils to infiltrate several regions of the brain, most notably in the vicinity of the diencephalic dopaminergic neurons where they may locally modulate neural circuits that control locomotor drive. List of effects: black dot indicates normal/typical status, and downward arrow means a reduction. Reversal of the locomotor deficit in nlrc3l mutants by restoring wild-type macrophages indicates that the behavioral phenotype is driven by mutant inflammatory macrophages. Further optogenetic or chemogenetic manipulations of the proposed neural circuit are needed to validate the working model.