Project Summary/Abstract Rapid changes in eye position are used to reorient the eyes towards points of interest. Illuminating the mechanisms underlying the initiation of these movements can provide insight into oculomotor disorders typically characterized by involuntary movements such as saccadic intrusions. These involuntary movements obscure vision by changing the focus of the retinal fovea. Detailed functional studies, primarily in non-human primates, have resulted in models that propose that rapid eye movements occur when the activity of single neurons or neuronal populations rises above a threshold. However, direct evidence for this model is absent. The goal of this proposal is to provide structural and functional analysis of a cell type we have recently discovered whose activity suggests a role in saccade initiation; these cells show a consistent rise in calcium multiple seconds before saccades. We uncovered a disruption in saccade rate following focal laser ablations of populations containing these neurons. To find these cells, we took advantage of the small size, genetic and optical accessibility of the larval zebrafish brain to image calcium activity from single cells throughout the majority of the hindbrain while simultaneously tracking spontaneous eye movements. The cells we found were the only hindbrain neurons containing pre-saccadic activity. Based on these results, we hypothesize that these cells contribute to the neural circuit initiating spontaneous saccades. I propose two aims to elucidate role of pre-saccadic activity in triggering rapid eye movements. In the mentored K99 stage, I will characterize the activity of neurons with pre-saccadic activity during the fast phase of optokinetic stimulation and saccades using whole-brain calcium imaging and electrophysiology. I will refine the behavioral role of these neurons by reversibly silencing and activating their activity during stimulation (Aim 1; K99). Finally, I will assess how this neuron type interacts with other cell types in the oculomotor circuit and characterize the morphology of this cell class (Aim 2; R00). Collectively, these experiments will address unanswered questions in our understanding of how horizontal eye movements are generated. The training plan described in this proposal details a focused strategy for acquiring the necessary skills I need to successfully transition from a trainee to independent investigator. My principal mentor, Dr. Emre Aksay at Weill Cornell Medical College, and my exemplary team of co-mentors have been carefully chosen to provide the necessary experience and technical expertise to achieve this goal. Mentor counsel, recurring data presentations, attendance of seminars, conferences and professional courses will all be utilized to build the necessary communication and leadership skills vital to a successful scientific career. After transitioning to the independent phase, I will use these skills to establish a laboratory that uses interdisciplinary tools to study the neural basis of movement initiation.

PUBLIC HEALTH RELEVANCE: Everyday tasks such as reading and driving require a healthy eye movement control system in order to keep images in focus. The neuronal mechanisms that control voluntary eye movements are not well understood yet their disruption, due to disease or dysfunction, can have debilitating effects. The studies in this proposal seek to advance our understanding of these mechanisms with the goal of laying the groundwork for improved treatment when they go awry.