The gray, 2 mm-thick, fibrous covering known as the Cerebral Cortex comprises 90 percent of our brain. Yet no one knows how it works.
Columbia professor, and an investigator of the Howard Hughes Medical Institute, Rafael Yuste is applying innovative experimental techniques that straddle biology, physics, chemistry and engineering to figure it out. By developing a general theory of how the components of a healthy cerebral cortex works, Yuste says, neuroscientists could come up with better therapies for neurological and psychiatric disorders, such as epilepsy and schizophrenia.
But in order to put together that theory, Yuste is first developing laboratory tools to test it. His groundbreaking work with compounds that bind to chemicals and release them when hit with light could have applications that go far beyond the questions he is exploring in his lab.
Yuste, a native of Madrid, Spain, was first trained as an MD and then as a PhD. He spent a decade researching the cortex, at Rockefeller University and Bell Laboratories before landing at Columbia.
The cerebral cortex is hypothesized to be comprised of thousands of identical yet discreet modular circuits, which vary in function depending on what input plugs into them. The modules in the visual cortex contain inputs from the eyes, he posits, while the auditory modules receive sound inputs, yet both modules could work in the same fashion.
One way to understand how these fundamental building blocks of the brain work is to take one apart and map out how its component parts fit together, like an engineer would do with an electronic circuit board.
The traditional method of studying the way neurons work is to attach an electrode and wires to a piece of tissue and study the way a discreet neuron reacts to stimulus. But since Yuste is interested in figuring out how thousands of neurons work together in the cortical circuit, he needed to find a way to get thousands of neurons to react to a stimulus at will.
Together with his colleague Roberto Etchenique, an inorganic chemist from the University of Buenos Aires in Argentina, who spent a Fulbright sabbatical at Columbia University, Yuste developed what they call an “optical cage” that contains the metal Ruthenium. In the absence of light, the metal binds to and holds in place the chemicals, known as neurotransmitters, that make a neuron fire. But the ruthenium compound is light sensitive. When hit with a beam of light, the optical cage reacts by releasing its hold on those neurotransmitters, allowing them to make contact with the neurons nearby and signal them to become active.
To direct the light, Yuste and his group make use of a “spatial light modulator” (SLM): a black box smaller than an IPod with a computer that allows them to precisely shape the beam of light into any pattern they choose. “We can spell out ‘Columbia’ on a couple hundred microns,” he says. Using these techniques, Yuste can turn neurons on and off at will, tracking their activity and watching how the component parts of the circuit interact.
But his optical cages have many other practical applications, like stopping epilepsy. One collaborator is injecting into the brains of epileptic rats an optical cage that contains GABA, a neurotransmitter that shuts down brain cells. When a seizure starts, a light turns on that triggers the release of GABA. By releasing GABA with light, it is possible to stop epileptic seizures in animals and potentially treat epileptic patients with these compounds.
“These inventions could also be used to release drugs with light in the middle of the body for therapeutic reasons,” Yuste posits. “For instance: chemotherapy in cancer. You could take a pill with a “caged” anti-cancer chemical and the medicine would go throughout the body without causing any harm. If the patient had, let’s say, a liver tumor, you could then shine a light on the liver and the medicine would only be active there and destroy the tumor.”
To view technologies from Dr. Yuste's lab, please click here