Book Description

Currently there is no treatment for recovery of human nerve function after damage to the central nervous system (CNS). Many brain diseases and injuries involve the activation of innate immune cells to clear damaged neurons. The resident immune cells of the CNS are microglia, the primary cells that respond to infection and injury. These cells serve as key modulators of brain development and plasticity and have been shown to be important in the formation of neural connections and regeneration of neurons. This dissertation utilizes the zebrafish olfactory system as a model to investigate the ability of the adult brain to recover from damage by injuring the nose and examining the resulting effects on the brain. While the olfactory system is renowned for its ability to recover from damage, and microglia can support and shape brain tissue throughout life, the specific mechanisms of microglial involvement in olfactory system plasticity are not known. The primary objective of this dissertation is to demonstrate the role of microglia in neural regeneration after damage to the olfactory bulb and the significance of these innate immune cells in long-term functional recovery. Chapter II involves a morphological analysis of microglia that reveals varying activation states with different forms of damage, where a permanent form of injury will be compared with injury models that have a regenerative potential. Chapter III explores microglial proliferation after damage, demonstrating that there is an increase in resident microglia in the olfactory bulb from other brain regions, followed by the infiltration of peripheral macrophages, rather than local cellular proliferation. Chapter IV explores the kinetics of microglial recruitment, and how it corresponds with olfactory sensory neuron axonal degeneration and regeneration. Examination of this phenomenon will allow us to understand the microglial contribution in regeneration and lead us to potential cell-based therapies targeted at manipulating immune mechanisms involved in neurodegenerative disorders such as Alzheimer’s, Parkinson’s, stroke, or trauma. The body of this dissertation explores the microglial response to damage in the zebrafish, which are widely used in developmental and neuroplasticity studies, partly due to their regenerative nature. The zebrafish olfactory system is comparable in structure and function to other animals, including humans. This dissertation will further our understanding of the role of innate immune cells and inflammation in neural plasticity. These results will further our knowledge of microglial involvement in facilitating neural regeneration, with the goal of elucidating potential therapeutic models for long-term morphological and functional recovery after neuronal damage. Understanding innate immune cell behavior following neuronal damage may help to develop novel methods for treating toxic and chronic neuroinflammatory processes that are seen in brain trauma and disease.