Date of Award

8-2025

Degree Name

Doctor of Philosophy

Department

Biological Sciences

First Advisor

Christine Byrd-Jacobs, Ph.D.

Second Advisor

Erika Calvo-Ochoa, Ph.D.

Third Advisor

Pamela Hoppe, Ph.D.

Fourth Advisor

Cindy Linn, Ph.D.

Keywords

Chemical lesion, microglia, olfactory bulb, olfactory sensory neurons, qpcr, zebrafish

Abstract

Adult zebrafish regenerate neurons throughout their lifetime and exhibit rapid recovery from neuronal damage with support from their immune system, making them an excellent model for studying neuroinflammation and brain repair mechanisms. When olfactory sensory neurons are lesioned, their cell death stimulates the immune system by activating microglia and other immune cells in the olfactory bulb, initiating tissue repair and neuronal replacement. This dissertation investigates how the immune system influences recovery from neuronal damage, testing the hypothesis that immune perturbation in zebrafish alters neural recovery.

To investigate the link between immune function and neuronal regeneration, zebrafish received a unilateral lesion to the olfactory epithelium that resulted in olfactory sensory neuron death. In addition to the lesion, fish were treated with either an immune-activating compound, zymosan, or a vehicle control, saline. The lesion and resulting cellular death caused a breakdown of associated glomerular structures in the olfactory bulb where neurons synapse, followed by immune activation that was influenced by zymosan or saline injections. Fish normally recover within one week, but treatments altered that timeline, based on qualitative assessment of four distinct glomeruli over time. The extent of damage varied among glomeruli, likely related to the type of innervation, and recovery patterns differed depending on the immune-modulating treatment. The recovery process was explored further by investigating inflammatory gene expression. After 24 hours, immune-modulated fish had an upregulation of cxcl8a (also known as IL-8) mRNA, a pro-inflammatory cytokine, along with changes in expression of other pro- and anti-inflammatory genes. Vehicle control pretreatment led to a mixed inflammatory profile and delayed glomerular recovery. In contrast, concurrent treatment with zymosan promoted faster recovery of glomeruli. Modulating the immune system by injecting the pathogenic component zymosan led to faster resolution of damage and limited upregulation of the genes of interest, whereas saline may contribute to a prolonged or potentially chronic inflammatory response and more broadly upregulated genes of interest.

These findings highlight the importance of both the timing and type of immune stimulation in neuronal recovery. Understanding the mechanisms that support successful regeneration in zebrafish may inform therapeutic strategies for enhancing neural recovery in humans, where regeneration is typically limited.

Access Setting

Dissertation-Open Access

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