Neurons form precise and complex neural circuits to generate perception and behavior. A major goal of neuroscience is to map the large ensemble of neural circuits in the brain and understand how they account for normal brain functions and neurological disorders. The small size and optical transparency of larval zebrafish make it an ideal system to investigate neural circuits in an intact vertebrate organism. However, current techniques for mapping neural circuitry in zebrafish are limited in speed and scale, preventing the full realization of zebrafish's potential for neural circuit studies. To address this gap in technology, we propose to develop a virus-based toolkit that would enable rapid and systematic neural circuit mapping in zebrafish. In preliminary studies, we established that vesicular stomatitis virus (VSV) can be used as a tool to map neural circuits. It efficiently infects zebrafih neurons, spreads rapidly across synapses, and expresses fluorescent reporters for circuit mapping. VSV labeling could also be combined with other imaging methods to probe neuronal function. To extend these studies, we propose three specific aims:
Aim 1. We will establish virus-based tools to map neural circuits on a whole-brain scale, in vivo. We will investigate the characteristics of VSV and distribute reagents and neural circuit mapping results to the community.
Aim 2. We will develop tools to elucidate connectivity patterns of specific neuronal types. These tools will be able to (1) target initial infection to defined cell types and (2) identfy neurons that are directly connected to them.
Aim 3. We will create tools that combine neural circuit mapping with functional analyses. These tools will help bridge the gap between neural circuit structure and function. In summary, this proposal addresses a critical need for zebrafish neural circuit tracing tools and provides a novel approach to combine anatomical and functional analyses. We will utilize these tools to map the circuitry underlying visual function, both as a tet platform and as a resource for studying vision. These tools could be applied throughout the nervous system and facilitate neural circuit studies in the wider community, e.g. neural development, physiology, behavior, regeneration, as well as disease models.

Public Health Relevance

Detailed knowledge of the cellular architecture and physiological responses of neural circuits is necessary to understanding normal brain function and develop treatments for neurological disorders (e.g. autism, Parkinson's disease) or functional loss (e.g. blindness, spinal cord injury). The proposal would develop virus- based tools to identify and investigate zebrafish neural circuitry, which is structurally and functionall homologous to that of humans. These tools will enable rapid and systematic characterization of neural circuits underlying essential animal behaviors and provide insights to how these circuits affect human disease.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Greenwell, Thomas
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Georgia Regents University
Internal Medicine/Medicine
Schools of Medicine
United States
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Beier, Kevin T; Mundell, Nathan A; Pan, Y Albert et al. (2016) Anterograde or Retrograde Transsynaptic Circuit Tracing in Vertebrates with Vesicular Stomatitis Virus Vectors. Curr Protoc Neurosci 74:1.26.1-27
Mundell, Nathan A; Beier, Kevin T; Pan, Y Albert et al. (2015) Vesicular stomatitis virus enables gene transfer and transsynaptic tracing in a wide range of organisms. J Comp Neurol 523:1639-63