The Horizontal Oculomotor System in Zebrafish: Binocular Coordination, Functional Architecture and Early Maturation

Abstract

Die Dissertation ist gesperrt bis zum 10. Mai 2025 !

The oculomotor integrator transforms an eye velocity input into an eye position signal that is essential for retinal image stabilization. This signal is stored for a prolonged amount of time in the brain and acts as a working memory for eye position. The oculomotor integrator is embedded into the vertebrate hindbrain circuit that drives horizontal eye movements. While the basic components of this circuit are known, we still have little knowledge about how those neurons achieve this integration and the exact coding properties of those neurons and of the connected oculomotor nuclei. Similarly, different theories exist that try to explain how the binocular coordination of the two individual eyes is achieved to drive precise binocular eye movements. No conclusive answer has been found to this question so far. The larval zebrafish is becoming an increasingly popular choice for neuroscientists as a model organism due to its transparency and great accessibility for microscopy studies during early development. Therefore, I used calcium imaging in the developing brain of larval zebrafish to investigate those questions. In the first set of experiments, I exploit a specific experimental paradigm to provoke monocular eye movements in one-week old larval zebrafish to investigate the eye specific tuning of oculomotor neurons and to coarsely map their eye position/velocity sensitivity. I imaged the hindbrain area encompassing the nucleus abducens, oculomotor integrator, inferior olive, and the velocity storage mechanism. The results of this experiment show that the neurons of those nuclei can be grouped into four response groups which differ in their activity during monocular eye movements. One group shows preferential activity during binocular eye movements. This points towards a certain degree of task separation at this developmental stage. Additionally, I show how the oculomotor integrator appears to extend into areas that were previously not identified as important for retinal image stabilization. In the second part, I further investigate the precise tuning properties of those neurons by running a closed-loop experiment that was aimed at decoupling the eye position signal from eye velocity. I report how oculomotor neurons encode eye position and eye velocity to a varying degree and their different activation thresholds. I show how the neurons in the caudal hindbrain appear to integrate eye velocity into position along a gradient, but they are arranged in two separate eye position and eye velocity clusters. In the last set of experiments, I examine the maturation of the previously investigated nuclei. I replicate the experiments on two-week old larvae, as the brains of zebrafish are still developing at that age. I show how several aspects of the oculomotor system are already established in young larvae, but some others are still undergoing refinement. Monocular neurons increase their eye specific sensitivity even further and the eye velocity system is becoming almost exclusively monocular with age. Neurons that show preferential binocular activity are more distributed in the brain and become less frequent with age, while neurons that are active regardless which eye is moving become more abundant. This thesis characterizes the binocular coordination and coding sensitivities of the oculomotor hindbrain neurons at two different developmental stages. It expands our knowledge on how the nuclei controlling horizontal eye movements are tuned and provides the basis for further investigations on how persistent activity can be generated in the brain.