PROBING THE FUNCTIONAL AND MOLECULAR LANDSCAPE OF THE RETINA WITHIN DEVELOPMENT AND TIME-OF-DAY DIMENSIONS  FOR A ZEBRAFISH FASD MODEL AND BEYOND

Kemal Donlic

Fetal alcohol spectrum disorder is associated with widespread nervous system impairment, including retinal abnormalities and visual dysfunction. The developing retina is highly sensitive to impaired protein quality control, oxidative stress, and circadian disruption. This dissertation investigated how developmental ethanol exposure damages the retina and examined protective therapeutic strategies that may reduce ethanol-induced visual dysfunction. Using zebrafish as an in vivo model of developmental alcohol exposure, this work showed that binge-like ethanol exposure, during early retinal maturation following functional cone vision, impaired visually guided behavior and altered retinal function. These effects were associated with ethanol-induced damage to cone photoreceptor and inner retinal neurons following embryogenesis. In addition, ethanol also disrupted proteostasis in cone photoreceptors, supporting the hypothesis that impaired protein degradation and stress-response pathways contribute to retinal dysfunction. Pharmacological enhancement of the ubiquitin system protected visual function and may represent an important therapeutic target in ethanol-induced retinal damage. This dissertation further demonstrated that the timing of ethanol exposure strongly influences retinal vulnerability. Daytime exposure produced greater visual impairment than nighttime exposure implicating circadian state as a contributing factor that modulates the retinal response to ethanol. Gene expression patterns linked this time-of-day sensitivity to redox regulation and protein quality control pathways. Additionally, supplemental melatonin reduced ethanol-associated visual deficits in vivo and limited oxidative stress in photoreceptor-derived cells. These findings suggest that melatonin acts, at least in part, through antioxidant and proteostasis mechanisms rather than solely through receptor-mediated signaling and reinforces the daily protective role of melatonin in retinal physiology. Finally, this work evaluated therapeutic hypothermia as a potential intervention against ethanol-induced retinal damage. Mild hypothermia protected visual function following ethanol exposure and influenced the expression of genes involved in oxidative stress responses, protein homeostasis, and cold-stress adaptation. In contrast, elevated temperature did not provide comparable protection. These results indicate that hypothermic preconditioning can reduce ethanol-induced impairment of visual function by improving neuronal resilience under oxidative and proteotoxic stress. Together, these studies identify disrupted proteostasis, oxidative stress, and circadian vulnerability as interconnected mechanisms that drive ethanol-associated retinal dysfunction. The dissertation establishes the developing zebrafish retina as a useful model for studying visual deficits related to fetal alcohol exposure and highlights, proteostasis modulation, melatonin, and therapeutic hypothermia as promising strategies for protection of the developing visual system.

PROBING THE FUNCTIONAL AND MOLECULAR LANDSCAPE OF THE RETINA WITHIN DEVELOPMENT AND TIME-OF-DAY DIMENSIONS FOR A ZEBRAFISH FASD MODEL AND BEYOND

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