The human brain is composed of billions of interconnected neurons that form highly complex neuronal circuits that process information and encode behavior. Many questions about these interconnected networks are unanswered: How variable are they from individual to individual, how do they change throughout life, how does the environment impact on them, and what are the genetic blueprints that generate these networks. Disruptions of the genetic blueprints that build neuronal networks are the likely cause of many human neurological diseases. In order to study neuronal networks in the brain, it is of paramount interest to easily visualize the patterns of connectivity of neurons, ideally in the context of live organisms. The cellular complexity of brains prevents such types of studies in complex organisms, and this project therefore uses a simple invertebrate model system, the nematode C.elegans, to visualize all the major neuronal connections of its simple nervous system. Previous studies have amply demonstrated that mechanisms of brain patterning discovered in C.elegans are conserved in other animals as well. The investigators develop and use cutting-edge fluorescent reporter technology, combined with microscopical and computer vision technology to achieve this goal. The project's construction of animals in which most neuronal connections are fluorescently labeled provides a major resource. This resource is made available to the large field of C.elegans researchers who with that resource can study the many questions that relate to circuits in the brain, including the decoding of the nervous system's genetic blueprint. In addition, the project includes cutting-edge, interdisciplinary training opportunities for undergraduate and graduate students from diverse backgrounds, as well as postdoctoral fellows.
The project entails the development and dissemination of tools that empower the C.elegans neuroscience community to study the connectome of the nematode C.elegans. In the first phase, the technology hub develops two sets of tools: One group uses fluorescent-based reporter technology (GRASP and iBlinc as potential alternative) to generate a large number of transgenic C.elegans strains in which the main "edges" of the entire wiring diagram (i.e., pairwise combinations of neurons) are visualized. As part of this project, this resource is distributed throughout the C.elegans community to enable labs with long-standing interest in various aspects of neuronal development and function and with a focus on specific neuronal circuits and behaviors to use these synaptic labels to examine variability, development, and plasticity of these connections. In parallel, the other group develops microfluidic-based and automated image analysis technologies to precisely quantify the structure of the connectome and to enable high-throughput screening of worm population for defects in synaptic wiring. Computer vision and machine learning is used to score automatically disruptions of synaptic wiring to detect subtle changes in wiring. This NeuroTechnology Hub award is part of the BRAIN Initiative and NSF's Understanding the Brain activities.
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