With its 86 billion neurons and 100 trillion connections, the brain contains many more synapses than the galaxy does stars. A field of neuroscience known as connectomics charts these constellations of circuits and helps researchers understand the processes of neural development, plasticity, degeneration, and disease, yielding new therapeutic possibilities for conditions such as Alzheimer’s and Huntington’s Diseases. “This research helps us understand how the brain’s circuitry works,” said Hongwei Dong, associate professor of neurology at USC’s Stevens Neuroimaging and Informatics Institute and director of the CIC. “If you tell someone to come visit you in California, where should they go? We have really narrowed it down: I live in North Hollywood in this apartment building. This will help people in the future to really understand the pathways for diseases with specific symptoms.”
But generating a map of an organ as complex as the brain means collecting terabytes of data. Luckily USC’s new Center for Integrative Connectomics (CIC) is well equipped to tackle this challenge.
Dong’s expertise lies in neuroanatomy, where he has investigated the connections between hundreds of brain structures that coordinate to regulate behavior. In 2008, he used the data he collected from mice to create the Allen Reference Atlas (ARA), the first open-access brain atlas in the field.
The ARA serves as the architectural foundation for Dong’s Mouse Connectome Project (MCP), which traces bundles of neurons, or tracts, to map the brain’s functional networks. In a flagship paper, Dong and his team traced over 2,000 of the brain’s “cellular highways,” overturning the prevailing view that the cortex is a messy tangle of neurons by demonstrating its organization into distinct subnetworks. This insight earned Dong a high-profile paper in Cell, which was recognized as a landmark publication for the journal and was later featured in the 40 years of Cell timeline.
Building on these contributions, Dong’s proposed “Integrative Connectome” may be his most ambitious project yet. “It’s very important to look at neural circuitry globally, but also at cellular resolution,” said Dong. “We use different technologies to compare across animal models so we can get a comprehensive and integrative view of the entire neural circuitry.” While Dong’s previous work has employed manual tracing, viral tracing, and gene expression methods, his new Integrative Connectome will incorporate even more data modalities. This will require the use of highly advanced technologies to collect, integrate, and analyze data spanning anatomy, physiology, molecular genetics, behavior, and functional imaging. Dong envisions that this novel connectome resource will provide a “Google Map of the brain,” allowing users to toggle and overlay different views of the brain, just as Google Maps displays topography, street view, and satellite images, all within a standardized frame. Researchers will zoom in to examine specific structures, and zoom out to visualize the brain’s global wiring. The ultimate goal is to provide an intuitive way to compare data from individual studies against a standardized reference.
While neuroscientists have made significant progress toward understanding the structure and function of the brain, identifying classes of neuronal cell types has remained a challenge—one which the CIC plans to undertake. “Each of these anatomically-defined brain regions contains many different cell types that are positioned next to each other. Their connectivity may be different; their gene expression is different; their function is different,” Dong said. A single data modality, be it gene expression, neuromorphology, or connectivity, is not enough to accurately classify a cell type. Only by simultaneously examining all of these diverse properties will we develop a robust understanding of how each type of neuron works individually, and what contribution it makes to the broader network.
Classifying neuronal cell types is not simply a matter of anatomical precision; it has critical implications for understanding and treating neurological diseases. Identifying the properties of different cell types will help scientists develop tools to selectively manipulate them, and open doors for new targeted therapeutics with minimal side effects.
With this in mind, the CIC has moved beyond mapping healthy brains to investigate the neural circuitry underlying diseases such as Huntington’s Disease and autism.
“Our connectome will build bridges for all these knowledge gaps,” said Dong. “We build the normal connectome in order to understand how this connectivity is disrupted. Then we can begin to address different neuropsychiatric diseases.”
Zingg B, Hintiryan H, Gou L, Song MY, Bay M, Bienkowski MS, Foster NN, Yamashita S, Bowman I, Toga AW, Dong HW. Neural networks of the mouse neocortex. Cell 2014 156:1096–1111.Cell: Best of 2014
Hintiryan H, Foster NN, Bowman I, Bay M, Song MY, Gou L, Yamashita S, Bienkowski MS, Zingg B, Zhu M, Yang XW, Shih JC, Toga AW, Dong HW. The mouse cortico-striatal projectome. Nature Neuroscience 2016.http://www.nature.com/neuro/journal/vaop/ncurrent/nn.4332/metrics