Innate Immunity in Brain Development and Adult Homeostasis 203 views

Until recently, it was thought that the brain was an immune-privileged organ that functioned largely independent of the immune system during periods of health. It is now recognized that this concept is incredibly misconstrued. There is remarkable overlap in the evolutionary origins, organism development, and lifelong functioning of the immune and nervous systems. The studies presented in this dissertation emphasize this critical interplay between immunity and brain function. The fledgling neuroimmunology field has begun to uncover homeostatic roles for immune molecules in the nervous system. Moreover, studies of neurologic diseases aimed at developing treatments have identified both beneficial and damaging roles for immune cells and signal molecules in terms of pathology and outcomes. This dissertation melds smoothly into such concepts, as the studies presented herein illustrate harmful impacts of immune activation on brain development but also reveal a necessity for immune signaling for proper brain function. Perturbation to a mother’s immune system, including infection, stress, metabolic disease, and autoimmunity, have been linked to altered offspring neurodevelopment. We found that activation of the immune system during pregnancy led to robust immune signaling in maternal-fetal-interface tissue, and that this changed the trajectory of offspring neurodevelopment and behavior. Pharmacologic medication further transformed the immune signaling landscape of the maternal-fetal-interface and developing offspring brains exposed to maternal inflammation. These findings highlight the critical importance of taking the entire maternal environment into account—and in particular the immune landscape—when striving to understand offspring brain development. Recent studies have led to the appreciation that molecules originally characterized in the immune system are also used by nervous system cells for classically non-immune functions. We found that the immune-based inflammasome complex was activated throughout the adult brain in the absence of known immune triggers. The assembly of this complex was modulated by experience and age. A homeostatic role for the inflammasome is highlighted in this work by our findings that blockade of inflammasome activation notably influenced astrocyte-neuron communication, hippocampal physiology, and memory function. These data indicate a novel role for the inflammasome in the maintenance of healthy brain function. In summary, this dissertation stresses the critical interaction between the immune and nervous systems for proper brain development and lifelong function. Our work contributes to an improved understanding of how perturbations to the immune system can influence the brain. This body of work emphasizes that a delicate balance of immune signaling must exist to provide necessary healthy support of brain development and function without straying into pathogenic overactivation and harmful consequences.

PHD (Doctor of Philosophy)

Neuroimmunology; Maternal immune activation (MIA); Selective serotonin reuptake inhibitor (SSRI); Maternal-fetal interface; Innate immunity; Inflammasome; Hippocampus; Astrocyte

English

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2023-04-20