Development of brain-scale neural circuits underlying vertebrate visuomotor transformations

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ABSTRACT It remains considerably challenging to restore vision after developmental disturbances, such as congenital infantile nystagmus, and after injury or retinal degeneration. This is because the mechanisms establishing functional connectivity between retinal ganglion cells and their downstream targets in the brain remain poorly understood. This knowledge gap is partly because observing the functional emergence, stabilization, and maintenance of entire visual neural circuits is impossible in mammals. This project will leverage the strategic experimental advantages of the larval zebrafish, a vertebrate model system, to investigate the functional maturation of a conserved neural circuit underlying a visual orienting behavior, the optomotor response (OMR). This will form the basis for understanding how congenital disorders exert their effects and how new neurons added after initial circuit development can support healthy visual processing. Recently, we described the transformation of retinal visual motion signals into motor output and showed that it required many different types of neurons distributed across the brain. These neurons can be classified based on their diverse eye- and direction-specific response profiles, and they collaborate to compute how exactly visual scenes are moving. Fascinatingly, this collaboration supports stable behavior 5 days after fertilization, even though new neurons are added to the circuit throughout life. We will test the central hypothesis that after initial formation, the OMR circuit expands by adding new neurons in balanced response classes, permitting the continued execution of motion- guided behaviors. In Aim 1, we will test how the development of the behavioral repertoire and associated neural circuitry is affected by specific disruption of direction-selective retinal input. By training recurrent neural networks, we will generate predictive models of connectivity between direction-selective retinal ganglion cells and downstream targets. In Aim 2, we will investigate how the functional neural representations mature, and we will quantify the stability of individual neuronal responses over time. By computationally tracking all neurons, we will directly investigate the trajectory of new neuron functional integration into existing circuitry and determine how the balance of functional profiles varies over time and covaries with behavior. In Aim 3, will use holographic photostimulation to examine the role of activity in shaping ultimate circuit role for individual neurons. Together, these experiments will reveal how an entire motion-sensitive vertebrate circuit is functionally assembled, providing insight about the functional connectivity between retinal ganglion cells and their downstream partners and about the nature and utility of neurogenesis. These results will inform regenerative treatment strategies for developmental disorders or injuries to central visual processing areas.