Josh Huang’s Brain Traffic Control

Josh Huang, PhDBy Lindsay Key

When neurobiologist Josh Huang, PhD, visualizes the inner circuitry of the brain—which he has studied for more than twenty five years—he imagines it like a traffic map. When nerve cells in one brain region release a signal, the information speeds along highways, byways, and backcountry roads until it arrives at its next destination—another nerve cell in a different brain area. 

But without traffic control—or stoplights and stop signs strategically placed along the way—information might accelerate until it speeds out of control, causing a person to have a seizure. Inhibitory nerve cells are the traffic lights that are placed throughout the nervous system that keep the system in balance and route appropriate information flow; Huang is especially interested in likely the most powerful of them all—the chandelier cell.

True to their name, chandelier cells indeed look like the hanging lights that hover over fancy dining rooms; a single chandelier cell uses the “candlestick” region of its anatomy as signaling outputs to control hundreds to over a thousand excitatory cells.

For his doctorate work at Brandeis University, Huang studied the cellular and molecular basis of circadian rhythms in fruit flies, but during his postdoctoral research at MIT, he became focused on mammalian brain circuitry. In 2000, he joined the scientific faculty at Cold Spring Harbor Laboratory in Long Island New York and has spent the last twenty years developing genetic engineering tools to study brain circuitry, including chandelier cells.

“They have a very striking morphology and are thought  to have a very unique function, enacting a ‘veto’ power to large neural ensembles in brain circuitry,” said Huang, who joined the Duke faculty as a professor in the Department of Neurobiology in the School of Medicine in August 2020, recruited with support from the Duke Endowment to advance faculty recruitment in the sciences. “But currently they are still a mystery. One of our major successes is that we developed molecular genetic tools that allow us to visualize and manipulate this fascinating cell.”

The tools that Huang develops and uses rely on mouse genetic engineering that leverages the inherent molecular genetic profiles of diverse types of nerve cells to systematically visualize and manipulate them, because the intricate shape and wiring complexity of nerve cells in brain circuitry cannot be captured by routine staining methods. Chandelier cell represents a shining example of Huang’s decade long research program to systematically build genetic tools that enable researchers to visualize and study comprehensive set of inhibitory and excitatory brain cell types.  

Chandilere CellJosh Huang, PhD, has developed molecular genetic tools that allow him to visualize and manipulate chandelier cells, such as the one pictured here.

But even though Huang has visualized these inhibitory cells extensively in the laboratory and in mice, to understand exactly what role they play in human brain function and disorders, he needs to be able to visualize and explore these cells in the human brain itself. And to do that, he found an ideal opportunity at Duke. 

“As a basic scientist, the attraction and the motivation to come to Duke is to have a better link to the broad biomedical and engineering research community, especially translational and clinical scientists,” said Huang. “In order to understand these inhibitory cells’ role in many of the neuropsychiatric disorders plaguing society, we need to be able to systematically visualize and study different cell types, including chandelier cells the basic building blocks and computation units of human brain circuitry.”

For decades, observations in the lab have led scientists to hypothesize that chandelier cells are involved in the pathophysiology epilepsy and schizophrenia in humans, but much more research is needed in a collaborative basic and clinical research environment to determine that this is actually true. 

In order to accomplish this goal, Huang looks forward to working with faculty in his home unit, the School of Medicine’s Department of Neurobiology, as well as those in clinical departments such as the Department of Neurology and the Department of Neurosurgery. In addition, he envisions interactions with faculty in Biomedical Engineering and Computer Science in studying brain circuit function.

Nerve cells are unique, said Huang, in that they are the longest living cells in the body. Unlike skin or blood cells which divide and renew themselves frequently, most nerve cells are born and remain inside a person for the rest of their life, perhaps even up to 100 years.

“That is fascinating by itself,” said Huang. “Many of the devastating disorders, especially aging and Alzheimer’s disease, have to do with the brain because the nerve cells are aging together with the body in exactly the same time scale.”

It’s also challenging, though, because current observations show that regeneration is very limited in nerve cells. While scientists have found evidence that there may be some regeneration in the olfactory epithelium and a very small region of the hippocampus, this knowledge is still developing, said Huang. That’s what makes study of the brain cells so important—if we are stuck with the brain cells we have, we will need to find ways to fix these nerve cells if they fail or become dysfunctional.

“The brain to me has always been a fascination from the very beginning because it’s an organ that really defines humanity and it’s the only organ that studies itself,” said Huang.

Outside of work, he enjoys exercising his own brain by reading historical fiction, playing classical music on the violin, and spending time with his family.

 

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