Cathryn Cadwell Receives Grant Through NIH BRAIN Initiative

September 26, 2023

Cathryn Cadwell, MD, PhD, an assistant professor in the Departments of Neurological Surgery and Pathology, has been awarded a grant to develop new technology to map the complex network of connections between neurons. The award is one of 11 grants that the National Institutes of Health (NIH) announced today as part of the Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) Initiative.  

UCSF assistant professor of neurosurgery and pathology Cathryn Cadwell, MD, PhD.

The BRAIN Initiative, which was established in 2013, seeks to accelerate the development of technologies to study the cell types and circuits in the brain. This new round of funding for the initiative’s third project – known as the BRAIN Initiative Connectivity Across Scales (BRAIN CONNECTS) – supports researchers using sophisticated methods to learn about neural circuitry underlying behavior. 

Traditional approaches to investigate the wiring diagrams in the brain are difficult and time-consuming, with each experiment only showing the connections between a few neurons at a time. Now, Cadwell – working with Andreas Tolias, PhD, at Baylor College of Medicine, Anthony Zador, MD, PhD at Cold Spring Harbor, and Xaq Pitkow, PhD, at Carnegie Mellon University – is developing a high-throughput approach to map neural circuits.  

“This technology has the potential to completely change the game and allow us to identify thousands of connections in a single experiment,” Cadwell said. 

Microscopy image showing adult human tissue infected by the barcoded rabies virus (red). Image courtesy of Cathryn Cadwell, MD, PhD.

The scientists label the neurons with a genetically modified rabies virus that introduces unique “barcodes” into a defined population of cells. Using high-throughput sequencing, they can then determine which neurons are directly connected to each other by recovering the barcodes in the cells once the virus has spread. The scientists will be assessing how well the approach works by comparing to circuit maps of well-characterized regions of the cerebral cortex. 

Cadwell and her colleagues will also be testing how well the approach works in tissue samples from patients – a key step towards understanding the human brain. Her research group works closely with Edward Chang, MD, chair of neurological surgery at UCSF, and Joanna Phillips, MD, PhD, the director of the Neurosurgery Biorepository, to bring relatively healthy brain tissue samples not needed for diagnosis back into the lab. 

“We like to assume that things will be relatively similar in humans and that the tools that work in the preclinical animal models will translate, but that's an important empirical question that that we need to start asking,” she said. 

Cadwell adds that neuroscientists need new methods to overcome the challenges to studying the human brain – like the variation between individuals. 

“The more we can develop these scalable technologies that allow you to get a lot of information from a single specimen,” she said, “the more we're going to be able to learn from studies with patient samples.” 

These studies also help lay the foundation for future research on how alternations in neural circuitry may contribute to neurological disorders like epilepsy. “There’s a huge gap between what we understand about how the brain works in animal models and what we understand about human neurological disorders at the level of cell types and circuits,” Cadwell said. 

 

Projects funded by BRAIN CONNECTS: 

Electron microscopy pipelines to map the mouse brain  

Developing DNA sequencing tools to “barcode” and map neurons 

Novel imaging methods for human and non-human primate brains