Date of Award

Fall 2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

First Advisor

Greer, Charles

Abstract

Microglia are brain-resident immune cells responsible for both maintaining homeostatic conditions necessary for normal neurodevelopment as well as orchestrating the brain’s response to environmental insults. Research into how the immune system and nervous system concomitantly develop and interact will not only improve our understanding of normal neurodevelopment but may provide insights into therapy after brain injury. The innate immune function of microglia phagocytosis is now understood to be involved in the developmental events of neurogenesis and synaptic pruning. However, microglia are also the first-line responders to environmental insults such as infection, trauma or toxins. Thus, if these environmental insults occur during critical periods of development, the intrinsically deleterious effects of these insults may be compounded through the disruption of microglia’s normal activities. It is therefore important to understand the baseline functions of microglia during development that may be compromised before addressing their inflammatory properties after injury, especially during the perinatal and early postnatal period. The effects of microglia-mediated immune response during development may be of special relevance to the olfactory system, which is unique in both its vulnerability to environmental insults as well as its extended period of neurogenesis and neuronal migration. The work presented in this thesis examines how microglia maintain homeostatic conditions in the neuroblast migratory corridor of the rostral migratory stream (RMS) in the olfactory system during early postnatal development. We found that microglia intimately interact with radial glia and neuroblasts in the RMS prior to the formation of the glial tube and vascular scaffold. While microglia ablation did not impact the migratory capacity of neuroblasts, extended microglia depletion induced an accumulation of apoptotic neuroblasts within a broader migratory corridor. Our data suggest that a specialized microglia subtype expressing the phagocytic markers CD68, MERTK and CLEC7A is involved in maintaining RMS homeostasis during the first postnatal week. These findings illustrate the importance of microglia phagocytosis in maintaining homeostasis of the early postnatal RMS and may provide insights into how infection or trauma during development might exacerbate injury by disrupting microglia’s normal activities.

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