Brainbow: Novel tools for studying the development of neuronal circuits

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DESCRIPTION (provided by applicant): The organization of the human brain relies upon precise connectivity among hundreds of billions of neurons. The vast majority of these connections are established during nervous system development, when neurons find and connect to appropriate targets. To date, detailed studies of neuronal circuit development and maturation have been hampered due to technical limitations that prevent the clear visualization of many interacting neurons. New "Brainbow" transgenic mice, however, use random expression of multiple fluorescent proteins to allow for the clear identification of multiple individual components within complex neuronal circuits. These new tools greatly enhance one's ability to study neuronal connectivity and its development by allowing one to extract previously inaccessible information about specific neural circuits. Using confocal imaging methods, clear circuit diagrams can be constructed by direct visualization of the axons and dendrites of many interacting neurons throughout the nervous system. However, existing methods of image analysis are not sufficient for large Brainbow datasets, requiring new advancements in current techniques. This research proposal aims to create and utilize computer algorithms for automating the reconstruction of large neuronal datasets, and to generate new Brainbow mouse lines for improved analysis. These new tools will then be used to conduct a thorough investigation into how neuronal circuitry develops in the young cerebellum, and how cerebellar circuitry may form abnormally in an ataxic mouse model of the developmental cerebellar disease known as ataxia telangectasia. These studies will help to provide a better understanding of how neuronal circuits develop and function in the mammalian brain. PUBLIC HEALTH RELEVANCE The goal of this work is to understand how circuits form in the developing brain. There are a great deal of human disorders that arise when neurological development goes awry; a better understanding of brain circuitry can lead to appropriate treatments for disease. This research will develop new tools that will help us to understand the developmental mechanisms that lead to normal and abnormal connectivity within the brain.