Development of a novel model: Using songbirds to elucidate the pro-neurogenic role of microglia in healthy and natural neurodegenerative states

Abstract

Abstract Inflammatory cells like microglia exert beneficial effects on neuronal survival, synaptic maintenance, and circuit plasticity. Most research has focused on neural injury or insult; roles in normal development and homeostasis remain less clear. To characterize the behavior of microglia under non-pathological conditions, we exploit seasonal death and replacement of neurons in a sensorimotor brain region responsible for singing behavior in white-crowned sparrow, Zonotrichia leucophrys. The song control nucleus HVC incorporates 50,000 new projection neurons into an existing pool of 100,000 neurons within one week of transitioning to breeding conditions. Within four days of transitioning back to nonbreeding conditions, an equal number of HVC neurons dies. Seasonal neuronal death in HVC increases neural stem cell proliferation in the adjacent ventral ventricular zone. This growth and regression correlates to respective increases and decreases in song production rate and quality. We found that microglia activation mediates pro-neurogenic responses in each of two paradigms: (i) inflammation induced locally with lipopolysaccharide microinjection in HVC was sufficient to induce neural stem cell proliferation; (ii) inflammation, including activation of microglia, was necessary to induce neural stem cell proliferation following seasonal neuronal loss. Having established that activation of microglia drives pro-neurogenic responses under non-pathological conditions, we are enabling future mechanistic studies with essential genetic and molecular tools, including a high quality annotated genome and transcriptome, cell-type specific molecular markers, in vivo imaging, and CRISPR/Cas9 mutagenesis.