The Role of Microglia in Neuroblast Migration in the Olfactory System

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Project Summary: The Role of Microglia in Neuroblast Migration in the Olfactory System The olfactory system is unique in both its vulnerability to environmental insults and its regenerative capacity. Interneuron cell death in the olfactory bulb is ameliorated by the replacement of these cells with new neurons capable of integrating into previously established neural circuits. Microglia may be pivotal to this process, as they are first-line responders to cell death and are responsible for clearing debris. There has also been growing appreciation in recent years for the role these immune cells play in establishing neural circuits during development. Moreover, there is evidence that microglia may recruit neuroblasts targeted to the olfactory bulb to sites of injury following stroke. The mechanisms by which microglia may influence neuroblast migration is not well understood, but the olfactory system offers a tractable model. Thus, this project will explore the hypothesis that microglia influence neuroblast migration during development and in response to cell death in the olfactory bulb. Three independent questions examining how microglia may affect neuroblast migration in the olfactory system are addressed here. Aim 1 will characterize the distribution and morphology of microglia in the developing olfactory system. It is hypothesized that microglia morphology reflects functional states, and preliminary studies show that microglia exhibit a greater range of morphologies during the early postnatal period, including the presence of small “ameboid” cells along the path of migrating neuroblasts. These “ameboid” cells may play a functional role in neuroblast migratory streams. Aim 2 will test the hypothesis that microglia depletion results in arrested neuroblast migration during development. Preliminary data indicates that microglia closely associate with migrating neuroblasts in the olfactory system during development and prior to the formation of the astrocytic and vascular scaffold that guides these cells in adulthood. If microglia depletion results in neuroblasts clumping and dying before they reach their final destination in the olfactory bulb, it would suggest a functional role for microglia facilitating neuroblast migration during this developmental period. Aim 3 will test the hypothesis that microglia secrete molecules that influence neuron migration. Fluorescence in situ hybridization and immunohistochemical approaches will be used to examine the expression of microglia-secreted molecules along the path of neuroblast migration, both during development and in response to neuron cell death in the olfactory bulb. Understanding how microglia mediate neuroblast migration in the olfactory system will not only increase our understanding of olfaction but may pave the way for better therapies to mitigate neurodevelopmental disorders and neurologic injury.