Inflammation induced by natural neuronal death and LPS regulates neural progenitor cell proliferation in the healthy adult brain

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Inflammation is typically considered a negative response to injury or insult, however, recent advances demonstrate that inflammatory cells regulate development, plasticity, and homeostasis through anti-cytotoxic, pro-generative responses. Here, we extend analyses of neuroinflammation to natural neurodegenerative and homeostatic states by exploiting seasonal plasticity in cytoarchitecture of the avian telencephalic song control nucleus, HVC (proper name), in the songbird Gambel’s white-crowned sparrow (Zonotrichia leucophrys gambelii). We report that local injection of the endotoxin lipopolysaccharide into HVC of birds in both breeding (high circulating testosterone) and nonbreeding (low circulating testosterone) conditions increased neural progenitor cell proliferation in the nearby but distinct ventricular zone. Additionally, we found that oral administration of the anti-inflammatory drug minocycline during seasonal regression of HVC reduced microglia activation in HVC and prevented the normal proliferative response in the ventricular zone to apoptosis in HVC. Our results suggest that local neuroinflammation positively regulates neural progenitor cell proliferation, and in turn contributes to the previously described repatterning of HVC cytoarchitecture following seasonally-induced neuronal loss.

Significance Statement We demonstrate that natural reactive neurogenesis, or the birth of new neurons in the adult brain following non-injury induced neuronal loss, is depressed with oral administration of the anti-inflammatory drug, minocycline. Minocycline – an inhibitor of microglia activation – prevents reactive neurogenesis following seasonally induced neuronal loss in the avian telencephalic nucleus, HVC (proper name). Conversely, local inflammation, induced by microinjecting endotoxin directly into HVC, increases neural progenitor cell proliferation in the adjacent ventricular zone, which supplies HVC with new neurons. These findings contribute to the emerging role that neuroinflammatory cells play in regulating adult neurogenesis and promoting circuit homeostasis and regeneration and establish the avian song control circuit as a useful model for future studies examining mechanisms of neuroinflammation.

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